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Lecture Introduction into ORGANIC CHEMISTRY Alkanes

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Lecture Introduction into ORGANIC CHEMISTRY Alkanes Powered By Docstoc
					                                Bioorganic chemistry for Medicine students


                  Lecture 1 Introduction into ORGANIC CHEMISTRY, Alkanes


       Carbon unites with many elements to form a great variety of compounds that are found in
such substances as coal, petroleum, fabrics, plastics, and rubber. Other carbon compounds include
plant and animal tissues, sugars, proteins, starches, and cellulose. About 1 million carbon
compounds are known. The substances that contain carbon are called organic compounds, and
the science that deals with them is known as organic chemistry. This name arose because chemists
once thought that many of these compounds could be formed only by a vital force (a life process).
This was disproved in 1828 when the German chemist Friedrich Wöhler converted the compound
ammonium cyanate, NH4CNO, into urea (NH2)2CO.
           Before this, urea had been known only as a product of life processes. Today chemists
can make many of the products that formerly had been produced only by living plants and animals.
           What are the organic compounds we meet in our everyday life?
-   Ethanol -a simple organic molecule showing narcotic properties, causing (in the case of regular
    usage) alcoholic dependence.
-   Acetone – dimethylketone – substance, widely used and having many applications (f.e. – nail
    polish remover, solvent etc.)
-   Aspirin – acetylsalicylic acid -a famous anti-inflammatory drug
-   Ascorbic acid – vitamin C
-   Taxol – used in treatment for cancer
                                                                                                OH
                                                   O         OH                         HO
                                                       C
                                        CH 3                                                         O
             H3C CH 2                                             O        CH 3    HO           O
                              H3C C                                   C                 CH
                  OH                    O
                                                                      O                  CH 2
                                                                                   HO
             ethanole               acetone            aspirin                           vitamin C

                                       O               O

                                                H3C          O        O
                                        NH                                    OH
                                               O H3C                      CH 3
                                                                 CH 3
                                       HO      O
                                                                 CH 3              O
                                                                     O
                                                       H3C
                                                                  O         CH 3
                               taxol
                                                                  O

       These are only some examples of thousands organic compounds. Carbon compounds exist in
such number and variety because of the chemical properties of carbon. Carbon has four valence
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electrons that form covalent bonds. Since carbon is in Group IV A of the periodic table, it appears
to be midway between the metals and non-metals and has the ability to react with both types of
elements. The structure of the carbon atom is unique among atoms, allowing a great array of
compounds that are stable under normal atmospheric conditions and reactive in other situations.


       Carbon reacts as follows:


1. Carbon atoms have the unusual property of combining with each other to form rings or long
     chains. No other element does so as extensively.
2. Carbon will combine with many different atoms or groups of atoms. This property, together
     with the ability to form long chains, makes carbon the most versatile of all elements in forming
     compounds.
3.   Carbon forms many compounds that exist as isomers. Isomers are molecules with the same
     number and kinds of atoms, but in different arrangements--for example, CH3CHCI2 and
     CH2ClCH2Cl.


        Chemical Bond


        The outer shell electrons of atoms can interact with each other to form chemical bonds. The
exact nature of this bonding interaction depends largely on the electronegativities of the individual
atoms; bonds between atoms with large differences in electronegativity tend to be ionic, in which
electrons are fully donated from one atom to another, and bonds between atoms with identical, or
small differences in electronegativity tend to be covalent, in which the electrons are shared between
the two atomic centers. Ionic and covalent bonds represent the limits of bonding, and covalent
bonds between atoms with differing electronegativities will tend to be polarized, with the greatest
electron density being associated with the most electronegative atom; again, ionic bonds represent
the upper limit of this polarization.
Some examples:
                        Cl   Cl                NaCl               H3C CH 2
                                                                       Cl
                          covalent             ionic              covalent polarized
                             bond              bond                    bond
        Electrons surrounding atoms are concentrated into regions of space called atomic orbitals.
The sharing of electrons in a covalent bond occurs by overlap of the individual atomic orbitals.
Head-on overlap between energetically compatible orbitals generates sigma () bonds, while
sideways overlap (typically from adjacent p orbitals) generates pi () bonds.

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        Lewis Structures

        Molecules can be represented by electron-dot formulas or, more conveniently, by dash
formulas, where each dash represents a pair of electrons shared by two atoms:



                                             H H         Cl Cl

        These formulas are often called Lewis structures; in writing them we show only the
electrons of the valence shell.

                THE STRUCTURAL THEORY OF ORGANIC COMPOUNDS

        Between 1885 and 1861, August Kekule, Archibald Scott Couper and Alexander M.
Butlerov, working independently, laid the basis for one of the most fundamental theories in
chemistry : the structural theory. Two central premises are fundamental:
   1. The atoms of the elements in organic compounds can form a fixed number of bonds. The
        measure of this ability is called valence. Carbon is tetravalent, oxygen is divalent and
        hydrogen and (usually) the halogens are monovalent.
   2.   A carbon atom can use one or more of its valences to form bonds to other carbon atoms.

                                    C C                 C C             C C

                                    single              double           triple
                                     bond                bond            bond
   Hybridisation
        In typical organic compounds, carbon forms a total of four bonds with adjacent atoms (it
has a valence of four). The bonding geometry, however, differs from that predicted from the simple
utilization of outer classical shell orbitals, and the geometry is best described by hybrid
combinations of these orbitals. A hybrid constructed from one s- and three p-orbitals is termed sp3,
and forms four equivalent bonds, directed at the corners of a regular tetrahedron. This type of
bonding is observed in carbon atoms in which there are four sigma bonds and sp3 hybridization is
generally associated with tetrahedral geometry (109.5 degree bond angles).




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                                                                      Carbon
                                                                      atom


                                                   Molecule of methane


       A hybrid constructed from one s- and two p-orbitals is termed sp2, and forms three
equivalent bonds directed at the corners of an equilateral triangle (120 degree bond angles). The
remaining p-orbitals on sp2 atoms participate in -bond formation and adjacent sp2 atoms are said to
be connected by a "double bond"; one sigma bond and one -bond.
       The final hybrid which is common in organic chemistry is constructed from one s- and one
p-orbital, termed a sp-hybrid, and has linear geometry. The two remaining p-orbitals of each sp
atom participate in -bond formation with an adjacent sp center and form a "triple bond"; one sigma
bond and two -bonds.


                                             ALKANES (paraffins)
       As previously noted, a carbon atom in a molecule forms 4 bonds to other atoms. In this
family of compounds all bonds are single (2 electron) bonds and each carbon is bonded 4 times to
either other carbons or to hydrogens. Since atoms with 4 bonds and no lone pairs of electrons have a
tetrahedral geometry, each carbon atom in an alkane is tetrahedrally substituted.
       The simplest member of the alkane family has one carbon bonded to four hydrogens. The
name of this compound (CH4) is obtained by putting together the root name for one carbon (meth)
and the family name (-ane) to give methane.
       Other simple family members can be obtained by linking a number of carbons together in
chain and completing the valence of carbon (4) by adding hydrogens.
       Other simple unbranched alkanes:
          H3C CH 3      H3C CH 2                   CH 3                                     CH 3
                                  H3C                     H3C           CH 3 H3C
                             CH 3
            ethane      propane          butane            pentane                 hexane




                  heptane                           octane                             nonane      .
       Branched alkanes:
       Since carbon requires four bonds to other atoms, it is possible to form compounds in which
more than two other carbon atoms are bonded to a carbon: up to four other carbons, of course.
       Note: It is sometimes convenient to refer to a carbon atom as primary (1°), secondary (2°),
tertiary (3°) or quaternary (4°) according to the number of other carbon atoms directly bonded to it;

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further, this designation is extended to the non-carbon atoms (or groups) attached to that carbon.
Thus a 3° carbon has three other carbons bonded to it, and, for an alkane, one hydrogen which by
extension is termed a 3° hydrogen.




       Alkyl groups:
       A group of atoms that has unused valence (representing by dash) is called a group. The
group derived from alkanes (R-H) by removal of H atom are called alkyl groups (R-).The name of
alkyl groups is obtained by replacing the –ane of the corresponding alkane name by the suffix –yl.
                                                                                   CH 3
                         CH 4   H3C CH 3        H3C      CH 3        H3C
                        methane ethane                propane               butane

                                                                 H3C
                       H3C      H3C CH 2 H3C             CH 2                      CH 2
                       methyl     ethyl               propyl             n-butyl

       In more complex cases, the alkyl groups are named by prefixing sec- or s tert- or t- to the
alkyl name.
                   H3C            H3C
                     CH                       CH 2       H3C     CH                H3C C
                   H3C            H3C                                CH 3                  CH 3

                iso-propyl            iso-butyl            sec-butyl                      tert-butyl



       This possibility of having the same number and type of atoms bonded together in different
ways is called isomerism: isomers are compounds having the same molecular formula but
different atomic arrangements. In the alkane series, the number of possible isomers increases
dramatically with number of carbons as shown.


                       4-2, 5-3, 6 –5, 7-9, 8-18, 9-35, 15-4,347, 20-366,319.
       IUPAC nomenclature
       The IUPAC system of nomenclature deals with the presence of isomers in a very easy way.
       The smallest alkane to exhibit isomerism is butane with 2 isomers:
                                                                     CH 3
                                               CH 3
                                H3C                            H3C        CH 3
                                          A                          B




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         Isomer A has the four carbons in a chain and so is butane isomer B has three carbons in a
chain and the fourth carbon branching off the center. To name compounds such as this one, with
branches, use following IUPAC system rules:
   1. The longest carbon chain in the molecule is selected and the complex alkane is regarded as
         alkyl derivative of the parent alkane containing this chain.
   2. The positions of the substituents attached to the parent chain are determined by numbering
         this chain from the end which puts them on carbons having the lowest numbers.
   3. To write the IUPAC name of a complex alkane, the name of the substituents with position
         numbers indicated in front of them and arranged in alphabetical order, are prefixed to the
         name of the parent alkane. The substituent names are hyphened on either side, except the
         last one which is merged with the mane of the alkane.
   4.    If the same substituent appears on the parent chain more than once, the position numbers
         are separated by commas and the prefixes di, tri, tetra est., are used to indicate the number
         of time it appears.
 Following these steps, compound B is named: methylpropane.
            Let‟s name all five isomers of hexane:




                               hexane                     2-methylpentane




                   3-methylpentane         2,3-dimethylbutane           2,2-dimethylbutane

         Inspection of these isomers shows that the two methylpentanes (#2 and #3) and the two
dimethylbutanes (#4 and #5) differ only in the positions on the main chain of the methyl groups.
Such isomers are termed positional or constitutional isomers and as illustrated by the names of
these pairs of isomers, different constitutional isomers are distinguished by numbering the main
chain.




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                               Lecture 2 ALKANES (continuation)

Natural sources
       The two main sources of alkanes are natural gas and petroleum. Both of these substances are
frequently found together in underground deposits. Natural gas contains about 80% methane and
10% ethane, the remaining 10% being a mixture of higher members. Petroleum is a major source of
alkanes containing up to 40 carbons.
Methods of preparation
   1. Hydrogenation of alkenes or alkynes. (Ni-catalyzed, 200-300 C)

                                             CH 2           Ni/toC
                                                     H2
                              H3C                                     H3C         CH 3
                                      propene                                propane

                                                             Ni/toC
                               H C C H                H2                  H3C CH 3

                                      acetylene                              ethane

   2. Reduction of alkyl halides (nascent hydrogen from f.e. Zn / CH3COOH)
                                               Zn + CH 3COOH
                                  R    Hal                            R      H    HHal

                                               Zn + CH 3COOH
                                 H3C      I                           CH 4       HI
                              methyl iodide                           methane

   3. Decarboxylation of carboxylic acids. When the sodium salt of a carboxylic acid is heated
       strongly with sodalime (NaOH+CaO), a molecule of carbon dioxide is split off as carbonate
       and an alkane is formed.

                              R COONa               NaOH              R H        NaCO 3


                             H3C COONa              NaOH              CH4 + NaCO3

                                  sod acetate                         methane
   4. Kolbe‟s synthesis – electrolysis of the concentrated sodium salt of a carboxylic acid

                     R   COONa          2 H2O              R R        2 CO2       2 NaOH + H2


                   H3C COONa            2 H2O          H3C CH 3         2 CO2         2 NaOH + H2
                      sod acetate                          ehtane
   5. Wurtz synthesis. Alkanes are produced by heating of an alkyl halide (RHal) with sodium
       metal.


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                             R Hal    2 Na          Hal       R              R R       2 NaCl


                             H3C Cl        2Na + Cl           CH 3           H3C CH 3       2 NaCl

                         methyl chloride                                      ethane

       The reaction between two different alkyl halides and sodium metal gives a mixture of
       products.
                                                                                         CH 3                 CH 3
              H2C Br + Na + Br             CH 3                   H3C CH 2       H3C            H3C
             H3C
             ethyl bromide      methyl bromide                    ehtane          propane            butane

   Chemical properties
       Alkanes are relatively stable to common reagents such as acids, alkalis, oxidizing
agents at room temperature. This is due to the fact that the electronegativity of carbon (2.6)
and hydrogen (2.1) do not differ appreciably. C-C bond is non-polar, C-H is almost non-polar,
so polar reagents find no reaction sites on alkanes. However, alkanes undergo two types of
reactions:
   -   radical substitution reactions
   -   thermal and catalytic reactions
    Halogenation reactions
      Alkanes react with chlorine and bromine in the presence of UV light or at temperatures of
300-400  C, yielding a mixture of products.
                                                         h
                                   CH4 + Cl2                       CH3Cl + HCl
                                  methane                 methyl chloride

                                                          h
                                   CH3Cl + Cl2                       CH2Cl2 + HCl
                                                               mehtylene chloride
                                                          h
                                   CH2Cl2 + Cl2                      CHCl3 + HCl
                                                                    chloroform
                                                          h
                                   CHCl     3   + Cl 2               CCl4 + HCl
                                                                  carbon tetrachloride

       Ethane and the higher alkanes react with chlorine in similar way and all possible substitution
products are obtained.
       Propane contains two types (primary and secondary) of hydrogens. Therefore, it gives two
monosubstitution products. Generally speaking, a tertiary hydrogen is more readily replaced than a
secondary hydrogen. A secondary hydrogen is more readily replaced than a primary hydrogen.




       Mechanism
       Radical reactions can be divided into three stages:
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              initiation step – initial formation of radical species
              propagation step- a series of chain-reactions resulting in the formation of new
               radical species
              termination – when two radical react one another so that no new radicals are
               generated
       Let‟s examine the reaction between methane and chlorine:
       Initiation
                                                    h
                                      Cl    Cl                Cl +        Cl
                                                  or heat
       Propagation
                                     CH4 + Cl                CH3 + HCl

                                     CH3 + Cl2               CH3Cl + Cl

       Termination
                                           H + Cl                  HCl

                                           CH3 + Cl                 CH 3Cl


Iodination
       Iodine reacts with alkanes reversibly. The HI formed is a powerful reducing agent and is
capable of reducing the iodoalkane to alkane.
Fluorination
        Fluorine is most reactive. It reacts with alkanes explosively under most conditions.
Fluoroalkanes can be obtained by using fluorine diluted with nitrogen.
       Nitration
      This involves the substitution of a hydrogen atom of alkane with NO2 group. At r.t alkanes
do not react with concentrated nitric acid. However, when a mixture of alkane and nitric acid
vapours is heated at 400-500 C, one hydrogen atom of an alkane is replaced by a nitro group. This
process is known as vapour phase nitration.
                                                 400-500oC
                           H3C H       HNO 3                        H3C NO 2             H2O
                           methane                                 nitromethane
       Nitration can also be carried out by using diluted nitric acid, heating and 2 atm pressure –
this free radical process is known as Konovalov reaction.
                                                                                  NO 2
                                                            t, p
                             H3C CH 2            HNO 3                   H3C CH                H2O
                                  CH 3           10%                              CH 3
                             propane                                 2-nitropropane

       Mechanism:
       Initiation
                                      HO NO2                         HO        + NO2

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       Propagation

                         H3C CH 2         HO                    H3C CH              H2O
                              CH 3                                   CH 3
                                                                             NO 2
                         H3C CH          HO    NO 2                 H3C CH               HO
                              CH 3                                           CH 3

       Termination
                                    HO         HO                 H2O2

                                                                                  NO 2
                                  H3C CH            NO2                 H3C CH
                                       CH 3                                       CH 3
                                                                                  OH
                                  H3C CH            HO                  H3C CH
                                       CH 3                                       CH 3

       Sulphonation
       At ordinary temperatures neither concentrated nor fuming H2SO4 reacts with alkanes.
However, when alkanes are subjected to a prolonged reaction with fuming H2SO4, one H atom is
substituted by SO3H group.
                         R H         H2SO4                     R SO3H             H2O

                         alkane      fuming                   alkanesulphonic
                                                                 acid
       Sulfoxidation and sulfochlorination
       Alkanes react with SO2 and O2 (sulfoxidation) or SO2 and Cl2 (sulfochlorination) in presence
of UV light.
                                                      h
                             R H     + SO2 + O2                     R    SO 3H
                                                         h
                             R H     + SO2 + Cl2                    R    SO 2Cl




                                               Alkenes
       Alkenes – Structure
       As we have already discovered, the reactivity of alkanes is limited because of the strong -
bonds formed in the sp3 hybridized carbons. A very different set of reactions becomes possible
when the hybridization of the carbon is changed to sp2, in a class of compounds called alkenes.
These compounds are also called unsaturated hydrocarbons.
       A sp2 hybridized atom can only be bonded to three other substituents. A carbon with this
hybridization will form three -bonds, giving a flat, triangular molecular geometry. The fourth
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electron remains in the un-hybridized p orbital, perpendicular to the plane of the three  -bonds. A
similarly occupied p orbital will exist on the adjacent, hybridized carbon atom. These two loosely
held electrons will be shared between the two carbons atoms, in an electron "cloud" lying above and
below the plane of the molecules. This side-to-side overlap of two p orbitals is called a  -bond. So,
there will be two bonds holding these adjacent carbons atoms together, one  and one  -bond,
shown as a double bond (C=C). This is the source of the "unsaturation".
        This double bond arrangement prevents rotation about the carbon-carbon bond, so there is
only one possible conformation. If there are non-hydrogen substituents on the double bonded
carbons, the possibility for stereo isomers exists. We will use the designations "cis" and "trans". In
alkenes, these indicate whether the substituents are on the same or opposite sides of the double
bond.
        In naming alkenes:
 1. The longest continuous chain containing the double bond defines the parent compound.
 2. The carbons are numbered from the end that places the double bond at the lowest possible
number.
 3. Designate the molecule cis or trans as necessary.
 4. Name the substituted alkyl groups as was done for alkanes.
 5. Replace -ane ending with -ene.
 6. If more than one double bond is present, the positions of the bonds are given the lowest
possible numbers and di (for two) or tri (for three) etc. is added before ene (e.g. triene)
        Let's look at a few structures and name them:
                                                 C C     C1
                                                     3 2
                                               C   C C
                                               C5 C4     C
                                                6
                                               C

        The longest continuous carbons chain containing the C=C is 6 C long, with the double bond
between carbons 2 and 3. This makes it a 2-hexene. There are methyl groups on C5 and C2 and an
ethyl group on C3. So, this is 3-ethyl-2,5-dimethyl-2-hexene. Is it cis or trans? Neither. C2 has two
identical substituents on it, so their positions relative to the rest of the molecule don't matter. In
order for stereo isomerism to exist in alkenes, each of the double bonded carbons must have two
different substituents.
        Another example:
                                          C1    C2   C5     C6
                                                C 3 C4       C7
                                                C      C

        The longest carbon chain is 7, with the double bond between C3 and C4, making this a 3-
heptene. There are methyl groups on both C3 and C4, so this is 3,4-dimethyl-3-heptene. Is it a stereo
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isomer? Each of the double bonded carbons, C3 and C4, has two different substituents, so it will
need to be assigned either as a cis or trans isomer. The main chain components (numbered carbons)
all lie above the double bond, so this is cis-3,4-dimethyl-3-heptene. The trans isomer is shown
below:
                                                  C   C5     C6
                                                    3 4
                                                  C C         C7
                                           C1     C2    C

         Let's work from a name to a structure. What is the structure of trans-1,3-dichloro-2-methyl-
2-pentene?
First make the 2-pentene
                                             C1       C2 C3 C4
                                                             C5

         It is the trans isomer, so the chain has to lie on opposite sides of the double bond
                                                 C1
                                                 C2    C3
                                                       C4   C5

         Next add the substituents, Cl on C1 and C3, and methyl on C2.
                                            Cl    C1    Cl
                                                    2 3
                                                  C C
                                                  C   C4 C5

         The cis isomer is shown below:
                                            Cl    C1  C4 C5
                                                  C2 C3
                                                  C     Cl
         There are two "common" names of alkenes that you should know. Ethene, C2H4, is
commonly called ethylene and propene, C3H6, is called propylene.




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                                                 Lecture 3
   Alkenes Electrophilic Addition Reactions, oxidation of alkenes, polymerisation. Alkynes .
Methods of preparations:
   1. Dehydration of alcohols. When alcohol is heated in the presence of sulphuric acid at 140-
      180ºC, a molecule of water is eliminated.
                                       H         H2SO 4
                               R       C CH 2                            CH 2    + H2O
                                                t=1800C           R
                                     H OH
                                    alcohol                           alkene
                                                    H2SO 4
                                           OH                           CH 2     + H2O
                             H3C
                                                 t=1800C H3C
                                   propanol                       propene

       With unsymmetrical secondary and tertiary alcihols, elimitation can proceed in two ways
   and a mixture of alkenes is formed. In this case use Saytzeff rule. It says that when alternative
   exist, hydrogen is preferetially eliminated from the carbon atom with fewer number of hydrogen
   atoms.
                                          H2SO 4
                                   CH 3
                    H3C                                H3C              CH 3     H2C
                                          t=1800C                                          CH 3
                             OH
                       2-butanol                       2-butene 80%              1-butene 20%

   2. Dehydrohalogenation of alkyl halides. When an alkyl halide is heated with an alcoholic
      solution of sodium or potassium hydroxide, a molecule of hydrogen halide is eliminated and
      an alkene is formed
                                H      NaOH/alcohol
                              R C CH 2                                  CH 2 + HHal
                                  H Hal                       R
                              Alkyl halide                        alkene
                                                NaOH/alcohol
                                        Br                                   CH 2 + HHal
                            H3C
                                                                  H3C
                               propyl bromide                               propene

   3. Controlled hydrogenationof alkynes
                                                             Pd
                                   R            H + H2                          CH 2
                                                                        R
                                       alkyne                               alkene

   4. Cracking of alkanes
                                                           t=6000C
                                                                           CH 2
                                          H3C       CH 3
                                                                      R
                                              alkane                  alkene

Chemical properties



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       Alkenes are more reactive than alkanes. The most important reactions of alkenes are the
addition reacrion. In addition reactions of alkenes, the π bond is broken and two new σ bonds are
formed.
       The sp2-hybridized carbon atoms are rehybridized to sp3.

                            H                      Nu
                                                                                 Nu H
                         Ñ Ñ                            Ñ Ñ                      Ñ Ñ

              Electrophilic attack by proton     Nucleophilic attack

       A π bond is a weaker bond than a σ bond, and compounds containing π bonds are usually of
higher energy than similar saturated compounds. As a result, addition reactions are usually
exothermic.
       Electrophile is a reagent which can accept an electron pair in a reaction. The name
electrophile means "electron-loving" and indicates that it attacks regions of high electron density
(negative centres) in the substrate molecule. Electrophiles are electron-deficient.The may be
positive ion (including carbonium ions) or neutral molecules with electron-deficient centres.
Examples are: H+, Cl+, Br+, I+, NO2+, R3C+, RN2+, +SO3H, AlCl3, BF3.
       An electrophile can be represented by the general symbol E+.
       Nucleophile is a reagent which can donate an electron pair in reaction. The name
nucleophile means "nucleus-loving" and indicate that it attacks regions of low electron density
(positive centres) in the substrate molecule. Nucleophiles are electron-rich. The may be negative
ions (including carbanions) or neutral molecules with free electron pair.Example are: Cl -, Br-, I-,
CN-, OH-, R-CH2-, NH3, RNH2, H2O, ROH.
       A nucleophile can be represented by the general symbol Nu-.
       In our case the electrophile is proton, region of high electron density - double bond,
nucleophile – Nu, region of low electron density – carbonium ion.
       Addition of hydrogen
       Alkenes add hydrogen under pressure and in the presence of Ni, Pt or Pd catalyst to produce
saturated hydrocarbons.
                                                            Ni
                                               CH 2 + H2
                                                                   R     CH 3
                                        R alkene                    alkane

       Addition of halogen
               Halogens (Cl2 or Brr) react with alkenes readily to give dihalogen derivatives.
                                                                    Br
                                               CH 2 + Br2
                                                                         Br
                                     H3C                      H3C
                                           propene          1,2-dibromoprotane

               Mechanism of addition:
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                                                                  
                                                         Br        Br
                                                                                                     -Br
                                CH 2 + Br 2                        CH 2                     CH 2
                      H3C                            H3C                   -Br      H3C      Br
                                                        -complex                     complex

                                                              Br          Br

                                                          H3C

       Addition of H-X (hydrogen halides)
       Relative rate of reactivity of HX: HI > HBr > HCl > HF
  The strongest acid, HI, is the most reactive because it can most readily lose H+ to the π bond of
the alkene. The acid therefore acts as an electrophile and attacks the electrons of the bond.
                                                         H                                           Cl
                                                         H
           H3C               CH 3      HCl         H3C C C CH 3 + Cl                      H3C
                                                                                                      CH 3
              2- Butene                                  H                                2-clorobutane
Mechanism of Addition:
   1. An electrophile (proton) attacks system and forms a carbonium ion
   2. 2.Nucleophilic attack of the carbocation intermediate gives the product
  Markovnikov's Rule: When an unsymmetrical alkene reacts with a hydrogen halide, the
hydrogen adds to the carbon that has the greater number of hydrogens attached to it, and the
halogen adds to the carbon having fewer hydrogens.
                      H3 C                                    CH 3                  H 3C     Br
                             C CH 2 + HBr            H3C C          Br    and not      CH   CH 2
                      H3 C                                    CH 3                  H 3C    Cl
                                                                   Cl
                                CH 3 HCl
                                   +                                      and not                  CH 3
                                                                   CH 3

  The addition of HX to an alkene is regioselective. A regioselective reaction gives predominantly
one isomer of the product where more than one is possible. Attack occurs at a specific region (site)
of the molecule.
WHY?? Addition of the electrophile to an unsymmetrical alkene proceeds by way of the more
stable carbocation.

                                        H Br                       Br
                             H3C                                                     CH 3
                                    C CH 2          H3C C CH 3                   H3C C Br
                             H3C                            CH 3                     CH 3
                                                     a tertiary carbonium
                                     H3C                       ion
                                       CH CH 2
                                     H3C  a primary carbonium ion
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                                  Bioorganic chemistry for Medicine students
       Anti-Markovnikov Addition of HBr
       Sometimes HBr adds to an alkene in such a way that the bromide becomes attached to the
least substituted carbon.
       The formation of the anti-Markovnikov product has been observed when O2 or peroxides
(ROOR) are present in the reaction. These compounds readily form free radicals. These radicals can
react with HBr to then generate bromine radicals by abstracting a hydrogen atom.
                                                          ROOR
                                            CH 2 + HBr                              Br
                                                                         H3C
                              H3C
                                    propene                              1-bromopropane

       Addition of HHal to alkene derivatives with electron-withdrawing groups (CF3, COOH, NO2
and etc.) attached to the double bond proceeds as anti Markovnikov‟s addition.
                                            CH 2 + HBr                                       Br
                                                                             F3C
                              F3C

       Addition of water
        Addition of water can occur only in the presence of mineral acid (HCl, H2SO4) and an
alcohol is form according to Markovnikov rule.
                                                                                 OH
                                                                 H
                                             CH 2 + H2O
                                    R                                        R        CH 3
                                        alkene                               alcohol

       Oxidation of alkenes
       As distinct from alkanes, alkenes are easily oxidized by a great variety of agents – starting
from the oxygen of the air. Under mild reaction conditions – KMnO4 in water or acetone, at room
temperature, the π bond of alkenes is cleaved, yielding glycols – diatomic alcohols.
                                                       KMnO 4            OH
                                               CH 2                                OH
                                                      water, r.t.
                                        R                            R
                                            alkene                       glycol

       Under more forcing conditions – f.e. using of potassium dichromate in the presence of
sulfuric acid, the skeleton of the molecule is broken, giving a mixture of carbonic acids :
                                             K2Cr 2O7                    O
                                    CH 2                     R       C                HCOOH
                                              H2SO 4
                             R                                           OH
                                 alkene                                          acids




       Reactions of polymerization.




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                                Bioorganic chemistry for Medicine students
       The molecules of alkenes can react with each other, forming a long-chains – this class
of compounds is called polymers.
                                                     kat
                                     n       CH 2                 CHCH 2
                                     R                            R         n

ALKYNES
       In alkynes the carbon atoms are sp hybridized. They are attached to each other by a σ bond
and two π bonds (a triple bond). The σ bond results from the overlap of two sp hydrid orbitals. The
π bonds formed from the separate overlap of the two p orbitals from the two adjacent carbon atom.
The geometry of alkynes is linear.
Nomenclature
       The IUPAC names are obtained by dropping the ending –ane of the parent alkane and
adding the suffix –yne. If necessary the carbon chain including the triple bond is numbered from the
end nearest this bond. The position of the triple bond is indicated by prefixing the number of the
carbon preceding it to the name of the alkyne.
                                H3C
                                                CH         H3C              CH 3
                                     1-butyne                    2-butyne

       Remember: A triple bond has lower priority than a double one thus a triple bond gets lower
number than a double bond.
       Alkynes are sometimes named as derivatives of acetylene, the simplest alkyne. This form of
naming is useful when referring to the conjugate bases of alkynes, such as acetylide ion

          H C C H            H3C C CH                            C C                 H C C-Na +

           acetylene      methylacetylene            diphenyacetylene                sodium acetylide

Methods of preparation
   1. Dehydrohalogenation dihalides. Compound that contain halogen atoms on adjacent carbon
       atoms are called vicinal dihalides or vic-dihalides. Alkynes are obtained by treatment of
       vicinal halides or dihalides with halogens attached to the same carbon atom with alcoholic
       KOH.
                                       H Br
                                                       KOH
                                 R C C H                              R C C H
                                                      alcohol
                                       Br H
                                     vic-dihalide                           alkyne
                                        H H
                                                       KOH
                                 R C C H                              R C C H
                                                      alcohol
                                         Br Br
                                         dihalide                      alkyne



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                                   Bioorganic chemistry for Medicine students
   2. Dehalogenation of tetrahalides. When 1,1,2,2-tetrahalides are heated with zinc dust in
       alcohol, alkynes are formed.
                                           Br Br
                                                              Zn
                                     R     C C H                         R     C C H
                                                             alcohol
                                           Br Br
                                         tetrahalide                           alkyne

   3. Reaction of calcium carbide with water. Calcium carbide reacts with water to yield
       acetylene.
                               CaC 2 + H 2O                   H C C H + Ca(OH)2

Chemical properties
       Alkynes give the same kind of addition reaction as do alkenes. However, with alkynes the
addition may take place in one step or two steps, depending on conditions. BUT remember: alkynes
are less reactive than alkenes.
       Addition of hydrogen
       In the presence of Ni, Pt or Pd alkynes add up two molecules of hydrogen first forming
alkenes and finally alkanes.
                                            H2/Pt                        H2/Pt
                        R C C H                                 CH 2                           CH 3
                                                           R                           R
                         alkyne                             alkene                         alkane

       The reduction can be stopped at the alkene stage (cis-alkene) by using Pd poised with BaSO4
+ quinoline (Lindlar’s Catalyst).
                                                            Pd, BaSO 4
                                     R C C R'
                                                            quinoline
                                                                         R        R'
       Addition of halogen
       Halogens add to alkynes in two steps forming a dihalide and then tetrahalide. The
mechanism is the same as in case of alkenes.
                                                       X                                   X   X
                                          X2                            X2
                       R C C H                              CH                     R C C H
                                                       R       X                          X X
                          alkyne                        dihalide                       tetrahalide

       Addition of halogen acid
       Halogen acids reacts with alkynes in two stages via Markovnikov addition. The mechanism
is the same as in case of alkenes.
                                                    Hal                                    Hal H
                                          HHal                          HHal
                       R C C H                                CH                   R C C H
                                                       R       H                           Hal H

       Addition of water (Hydration)


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                                    Bioorganic chemistry for Medicine students
         Alkynes reacts with water in the presence of mercuric sulphate and sulphuric acid to form an
aldehyde or a ketone. The addition of one water molecule gives an ENOL (i.e. "ene" (C=C) with an
alcohol group ("ol") attached. In acidic condition, this enol very rapidly converts to a ketone which
is the product.


                                                                    H                                 O
                                                HgSO 4
                    R C C H + H2O                        R       C C H                       R    C
                                              H2SO 4                                                  CH 3
                                                              O H
                       alkyne                                enol (unstable)                 ketone

         Only in case of acetylene you can obtain aldehyde (acetaldehyde).
         Addition of alcohols
         Alcohols can be added to alkynes in the presence of an alkali (an alcoholate) or a complex of
boron to yield vinyl ethers.
                                                                 NaOH           R        H
                                R             H + R'OH
                                                                           R'O           H

         Adddition of acids
         Alkynes react with acids in the presence of mercuric sulphate and sulphuric acid to give
alkenyl esters.
                                                             O                       R        H
                                                                   Hg 2+
                           R            H +        R'    C                 R'
                                                             OH    H                 O        H
                                                                            O

         Salt formation
         Acetylene and 1-alkynes are acidic in nature because they readily donate protons to strong
bases.

                           R C C H + Base                         R C C             + H-Base

         The acidity of acetylene or 1-alkynes can be explained by the atomic orbital description of
the C-H bonds. We know that s electron are closer to the nucleus than are p electrons. Therefore,
the more s character there is in a hydrid atomic orbital, the close the electrons of the bond are to the
nucleus. Thus the electrons of the C-H bond in 1-alkynes are more strongly held by the carbon
nucleus. This makes it easier to remove the hydrogen as a proton.
         Acetylene or 1-alkynes can react with sodium in liquid ammonia, sodium amide, with
ammoniacal solutions of cuprous chloride, silver nitrate to form acetylide of these metals.
                                       liquid
               R C C H + Na                        R C C Na
                                       NH 3
                  alkyne                         sodium acetylide
               R C C H + 2AgNO3+ 2NH4OH                              R C C Ag + 2NH4NO3 + 2H2O
                alkyne                                           silver acetylide
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                               Bioorganic chemistry for Medicine students
       Sodium acetylides react with primary alkyl halides to yield higher alkanes.

                        R C C Na + R'Hal                     R C C R' + NaHal

       Since 2-alkynes do not form acetylides, this reaction can be used to distinguish 2-alkynes
from 1-akynes.
       Oxidation
        Under mild reaction conditions – KMnO4 in water or acetone, at room temperature, the two
π bonds of alkynes are cleaved, yielding diketones.

                                                 KMnO 4        O      O
                                R C C R'
                                               water, r.t.
                                                               R     R'
       Under more forcing conditions – f.e. using of potassium dichromate in the presence of
sulfuric acid or potasiun permanganate, the skeleton of the molecule is broken, giving a mixture of
carbonic acids:
                                                              O             O
                                         KMnO 4
                          R C C R'                    R C            R C
                                         H2SO4
                                                              OH            OH




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                                Bioorganic chemistry for Medicine students




                                               Lecture 4
                          Electronic effects in organic chemistry. Dienes
       In this lecture we will consider two main electronic effects – inductive and mesomeric.
       Inductive effect
       It involves σ electrons (the electrons of σ-bond). The σ electrons which form a covalent
bond are seldom shared equally between the two atoms. This is because different atoms have
different electronegativity values. Therefore electrons are displaced towards the more
electronegative atom. This produces a certain degree of polarity in the bond. The more
electronegative atom acquires a small negative charge (δ-). The less electronegative atom acquires a
small positive charge (δ+).
       Consider the carbon-chlorine bond. As chlorine is more electronegative, it will become
negatively charged with respect to the carbon atom.
                                                      
                                                  C     Cl


       The arrow head indicates the direction in which the electrons are drawn.
       The inductive effect (I effect) refers to the polarity produced in a molecule as a result of
higher electoronegativity of one atom compared to another.
       The carbon-hydrogen bond is used as a standard. Zero effect is assumed in this case. Atoms
or groups which lose electrons towards a carbon atom are said to have a +I effect. Such groups are
usually called electron-donating groups. Those atoms or groups which draw electrons away from
a carbon atom are said to have a –I effect. Such groups are usually called electron-withdrawing
groups.
       Some common atoms and groups which cause +I or –I effect are shown below:
          -I effect groups: NO2, F, Cl, Br, I, OH, C6H5-, CF3, SO3H, CN, NH2 and so on.
             +I effect groups: (CH3)3C-, (CH3)2CH-, CH3CH2- CH3- (all alkyl groups).
        An inductive effect is not confined to the polarization of one bond. It is transmitted along a
chain of carbon atom, although it tends to be insignificant beyond the second bond.
       Mesomeric effect
       It involved π electrons of double and triple bonds.
       The mesomeric effect refers to the polarity produced in a molecule as a result of interaction
between two π bonds or a π bond and a lone pair of electrons.
       The mesomeric effect is of great importance in conjugated compounds in which the carbon
atoms are linked alternatively by single and double bonds.


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                                Bioorganic chemistry for Medicine students
       The mesomeric effect is represented by a curved arrow. The head of the arrow indicated the
movement of a pair of π electrons. The mesomeric effect does not fade along the conjugated chain.

                                                     H

                                          H3C
                                                           O 
       The mesomeric effect like the inductive effect can be positive or negative. Atoms or groups
which lose electrons towards a carbon atom are said to have a +M effect. Those atoms or groups
which draw electrons away from a carbon atom are said to have a –M effect.
       Some common atoms or groups which cause +M ot –M effects are listed below:
                         +M effect groups: Cl, Br, I, NH2, OH, NR2, OCH3
                          -M effect groups: NO2, CN, CHO, COOH, COR
       The inductive and mesomeric effects indicate the charge distribution in a molecule. Thus
they provide an effective way of determining the point of attacks of electrophiles and nucleophiles
on the molecule.
                                                DIENES
       Many hydrocarbnons are known whose molecules contain more than one double bond. A
hydrocarbon whose molecule contain two double bonds is called alkadiene. The multiple bonds of
polyunsaturated compounds are classified as being cumulated, conjugated or isolated. The double
bonds of allene (1,2-propadiene) are said to be cumulated because one carbon participates in two
double bonds. Hydrocarbons whose molecules have cumulated double bonds are called cumulenes
or allenes. In conjugated dienes double and single bonds alternate along the chain. If one or more
saturated carbon atoms intervene between the double bonds of an alkadiene, the double bonds are
said to be isolated.
       The double bonds of isolated dienes behave just as their name suggests- as isolated “enes”.
They undergo all of the reactions of alkenes, and except for the fact that they are capable of reacting
twice, their behavior is not unusual. Conjugated dienes are far more interesting, because we find
that their double bonds interact with each other. This interaction leads to unexpected properties and
reactions.
       Examples of dienes.

                           H2C C CH 2

                            cumulated           conjugated          isolated

Nomenclature
       Dienes are named by the IUPAC system in the same way as alkenes except that ending –
adiene are used. The position of the double bonds are numbered to give the first carbon of each
double bond a minimum number.


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                                   Bioorganic chemistry for Medicine students



                                     1,3-butadiene        1,4-pentadiene

Methods of preparations
   1. Heating of 1,4-dihalogenalkanes with alcoholic KOH. This is a dehydrohalogenation
       reaction.
                                                        KOH
                            Cl
                                                 Cl     alcohol
                                 1,4-dichlorobutane                     1,3-butadiene

   2. Acid-catalyzed dehydration of 1,4-alkanediols.

                                                          H
                            HO
                                                 OH
                             1,4-butanediol                              1,3-butadiene

   3. Lebebiev reaction. It is the industrial method for the preparation of butadiene from ethanol.
                                                 MgO, ZnO
                                            OH
                                                 400-500oC
   4. The industrial method of getting isoprene.
                                                 Cr 2O3, Al2O3, Cu 2+

                                                       500oC
                                   2-methylbutane                       isoprene

Chemical properties
       Addition of halogen acids
       1,3-Alkadienes react with halogen acids (HCl, HBr) to yield a mixture of two compounds.
The first product results from 1,2-addition to one of the double bonds. The second product results
from 1,4-addition (addition to terminal (1,4) position) with the formation of a new double bond
between C-2 and C-3. At low temperature (-80 C) the 1,2-product is preferred, whereas at higher
temperature (40 C) 1,4 addition predominates.
                                                        Br
                             + HBr                                   +                   Br
                                                     H                     H
                   1,3-butadiene                 3-bromo-1-butene          1-bromo-2-butene
                                                   1,2-addition              1,4-addition

       Mechanism:
       HBr can ionize to give a proton (electrophile) and a bromine ion (nucleophile). Proton
attacts a double bond according to Markovnikov rule to yield a resonance-stabilized carbonium ion
(resonance structure A and B). So bromine ion combines with A to give 3-bromo-1-butene (1,2-
addition). Whereas it combines with B to give 1-bromo-2-butene (1,4 addition). Thus a mixture of
two compounds is obtained.
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                                Bioorganic chemistry for Medicine students
                                                                                     Br
                                                                      +Br
                               + HBr
                                           -Br              A
                                                   H                            H


                                                                      +Br
                                                                                                 Br
                                                    H       B                   H
       Addition of halogen
       Dienes react with halogen in the presence of inert solvent (CCl4) to give a mixture of two
compounds because of 1,2-addition and 1,4-addition.
                                                   Br

                            + Br2                                    +                      Br
                                                 Br                         Br
               1,3-butadiene                3,4-dibromo-1-butene             1,4-dibromo-2-butene
                                                 1,2-addition                  1,4-addition

       Mechanism:
                                                                Br
                                           + Br2           Br

                                                                                -Br
                                                            -complex Br
                                                           -Br

                                            Br                             Br
                                                          -Br
                                                                                       Br
                                       Br                             Br

       Addition of hydrogen
       Dienes react with H2 in the presence of a catalyst to give a mixture of two products (alkenes)
which in the excess of H2 can be reduced to alkanes.
                                    + H2                                    +
                    1,3-butadiene                       1-butene                     2-butene
                                                       1,2-addition                 1,4-addition

       Only one product (1,4-addition) is obtained if dienes are reduced by sodium in alcohol.
                                                   Na+EtOH


                               1,3-butadiene                          2-butene
                                                                     1,4-addition

       Diels-Alder reaction
       This involves the treatment of conjugated dienes with an alkenes. The alkenes used in Diels-
Alder reaction is referred to as dienophile. The product of Diels-Alder reaction is called adduct.



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                                Bioorganic chemistry for Medicine students

                                          +
                                                  R                         R
                                  diene       dienephile           adduct

       Polymerization
       Dienes polymerize to yield two polymers, the result of 1,2- and 1,4-polymerizations.

                                                                       +
                                                               n                    n

                                              1,2-polymerization            1,4-polymerization

Caoutchouc (rubber) and gutta-percha
       Rubber is cis-1,4-polyisoprene. In industry it is obtained from latex of rubber-bearing plants.

                                                 CH 2 H2C

                                               H3C         H
                                                                   n

       Gutta-percha is trans-1,4-polyisoprene.

                                                 CH 2      H

                                               H3C      H2C
                                                                   n

       Rubber has high flexibility and plasticity but gutta-percha has not. Such a various behavior
of these two polymers can be explained by the different way of the packing of molecules. Therefore
gutta-percha having a closer packing of molecule then rubber shows worse stress-strain properties.




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                                Bioorganic chemistry for Medicine students



                                               Lecture 5
                                        Aromatic compounds
       The term “aromatic compounds” was first used by Kekule to classify benzene and its
derivatives, many of which possessed fragrant odour or “aroma”. Now, the term aromatic
compounds (arenes) stands for the whole series of compounds which contain one or more benzene
rings in their molecule.
Sources
   1. Carbonisation of Coal. When coal is heated in steel retorts at high temperatures out of
       contact with air, it carbonizes to coke. The process, called carbonization or coking is
       accompanied by evolution of gaseous products. On condensation, these products yield black
       viscous oil, (the coal tar) and the coal gas. The distillation of the coal tar gives a large
       number of aromatic compounds, among them – benzene, toluene, xylene, phenol and so on.
   2. Petroleum. C6-C8 fraction of petroleum is heated over Pt-Re-Al catalyst (platforming).
       This process converts alkanes and cycloalkanes to arenes.




                            hexane             cyclohexane           benzene

Criteria for aromaticity
   1. An aromatic compound is cyclic and planar.
   2. Each atom in an aromatic ring is sp2 hybridized and there exists a system of the conjugated
       -bonds.
   3. This cyclic electron cloud must contain (4n+2) π electrons, where n is integer (0, 1, 2, 3…).
       This is known as Huckel Rule.




                           aromatic non-aromatic non-aromatic        aromatic



Chemical properties
       The principal types of reactions of benzene are:
   1. Electrophilic substitution reactions
   2. Addition reactions
   3. Oxidation reactions
Electrophilic substitution reaction
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                                 Bioorganic chemistry for Medicine students
 Benzene undergoes electrophilic substitution reactions. The benzene ring with its delocalized π
electrons is an electron-rich system. It is attacked by electrophiles, giving substitution products.
This reaction can be represented as:
                                     H                                            E
                                                       catalyst
                                         + E-Nu                                        + H-Nu


       Such reaction in which hydrogen atom of the aromatic ring is replaced by an electrophile are
called electrophilic aromatic substitution reactions.
       General mechanism
       All electrophilic aromatic substitution reactions follow the same three-step mechanism.
       Step 1: Formation of electrophile.
                                                                    +
                              E Nu + catalyst                 E         + Nu-catalyst

       Step 2: The electrophile attacks the aromatic ting to form a carbonium ion.

                                   + E+                           E+                        E
                                                                                      H
                         benzene                   -complex                 carbonium ion

       The intermediate ion is resonance-stabilized. It is a hydrid of the following three structure:


                                     E                          E                             E

                                 H                          H                             H

       Step3: Loss of proton gives the substitution product.


                                                   E
                                                       -H
                                                                              E
                                               H

       Why benzene undergoes electrophilic substitution reactions, whereas alkenes undergo
addition reaction? Both benzene and alkenes are susceptible to electophilic attack because of their
exposed π electrons. The reason for this is the stability of aromatic systems (if benzene undergoes
an AdN reaction – the product would have no more been aromatic).
       Halogenation.
       Benzene reacts with halogens in the presence of Lewis acids (AlCl3, ZnCl2, FeBr3 and so on)
at room temperature.
                                                        FeCl 3                    Cl
                                              + Cl2

                                 benzene                          chlorobenzene
       Mechanism



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                                  Bioorganic chemistry for Medicine students
                                 Cl     Cl + FeCl       3              Cl+ + FeCl4-


                      + Cl+                 Cl +
                                                                             Cl                       Cl
                                                                         H                        H


                                                   Cl
                                                                                  Cl
                                              H

       Nitration
       Benzene reacts with nitric acids in the presence of concentrated sulphuric acid at 60ºC to
form nitrobenzene.
                                                                                  NO 2
                                                   H2SO 4
                                      + HNO3                                              + H2O


                          benzene                                     nitrobenzene

       Mechanism
       The mechanism of nitration and other electrophilic substitution reactions is the same as in
the case of halogenation. Only the first step – the formation of the electrophile – is different. So
farther we will give only the source of the electrophile.
       The formation of the electrophile.
                              HNO3 + H2SO4                           NO2+ + HSO4- + H2O

       Sulphonation
       Benzene reacts with concentrated sulphuric acid at 120ºC or fuming sulphuris acid at room
temperature to give benzenesulphonic acid.
                                                                                  SO 3H
                                      + H2SO4                                             + H2O


                          benzene                             benzenesulphonic acid

       The formation of the electrophile
                              H2SO4 + H2SO4                      HSO3+ + HSO4- + H2O

       Friedel-Crafts alkylation
       Benzene reacts with alkyl halides in the presence of Lewis acids to yield alkylbenzenes.
                                                                                   CH 3
                                                            AlCl 3
                                        + CH3Cl                                            HCl


                              benzene                                   toluene

       The formation of the electrophile.
                                  CH3-Cl + AlCl3                         CH3+ + AlCl4-

       Friedel-Craft Acylation

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                               Bioorganic chemistry for Medicine students
       Benzene reacts with anhydrides in the presence of Lewis acids to give aromatic ketones.
                                                                         O
                                              O                          C
                                                   AlCl 3                     CH 3
                                     H3C C                                            HCl
                                              Cl
                         benzene                         methylphenylketone

       The formation of the electrophile.
                                      O                             O
                                                                            -
                              H3C C        + AlCl3             H3C C + AlCl4
                                      Cl

Addition reactions
       Addition of hydrogen
       Benzene reacts with hydrogen in the presence of nickel (or platinum) catalyst at 150ºC under
the pressure to form cyclohexane.
                                                        Ni
                                               + H2


                                    benzene                   cyclohexane

       Addition of halogens
       Benzene reacts with chlorine in the presence of ultraviolet light to yield benzene
hexachloride.
                                                                   Cl

                                                   UV    Cl              Cl
                                       + Cl2
                                                         Cl              Cl
                                                                Cl
                                  benzene               benzene hexachloride

Oxidation reaction
       Ozonolysis
       Benzene reacts with ozone to give a triozonide which on treatment with Zn/H2O yields
glyoxal.
                                             O3
                                                                   H2O        H       O
                                     O3                                           C
                                                              O3    Zn            C
                                                                              H       O
                                             O3
                           benzene                   triozonide               glyoxal

       Vapour phase oxidation
       Benzene undergoes oxidation with air/oxygen in the presence of vanadium pentoxide at
450ºC to form maleic alhydride.



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Bioorganic chemistry for Medicine students
                                O
                  V2O5
           + O2                   O


                               O
 benzene              maleic anhydride




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                                 Bioorganic chemistry for Medicine students
                                                      Lecture 6
                               Aromatic compounds. Phenol, aniline
       When electrofilic aromatic substitution occurs on the ring already bearing one or more
substituents, the nature of that substituent will impact both the rate of the reaction and the
regiochemistry of the reaction (where on the ring the substitution occurs). In the table shown below,
the ring with activating substituents will react faster than benzene itself, and with deactivating
substituents will react more slowly. Further, substituents are grouped into two categories; ortho-,
para-directing and meta-directing.
                  strongly activating

                                  -NH 2
                                        -OH
                                  -OCH 3
                                                   NH
                                   -CH 3             C CH 3
                                                                  ortho and para directing
                                                   O
                                     -H
                                     -F
                                           -Cl
                                     -Br
                                           -I

                                   -CHO
                                                -COOR
                                                -COOH             meta directing
                                                        -COR
                                  -SO3H
                                                -CN
                                     -NO 2
                                                -NR3+
                 strongly deactivating

       A substituent is activating if it releases electron density into the ring either inductivity, or
through resonance (the electrophile is, after all looking for electrons; the more electron density, the
faster the reaction). The orientation effect is seen by considering the family of resonance forms
which can be drawn for a substituent such as an alkoxy group; these clearly show enhanced electron
density localized ortho- and para- to the point of attachment.
       Meta-directing substituents such as the nitro group can be seen to function by removing
electron density from the ring ortho- and para position to themselves, leaving only the meta-
positions with sufficient electron density to support the electrophilic (electron-seeking) reactions.
Thus, meta-directing substituents don‟t really activate the meta-position towards substitution, they
deactivate everywhere else.
       Halogens are somewhat unique in that they deactivate inductively (and are therefore less
reactive than benzene), but they direct to ortho- and para-positions since they enhance the electron
density at these positions by resonance, as shown below.




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                                Bioorganic chemistry for Medicine students

                    Cl                    Cl                          Cl                        Cl




       Halogens are deactivating inductively, but activate the ring through resonance.
       When there are multiple substituents on a ring, the effects are generally either cumulative, or
the most strongly activating substituent ultimately directs the regiochemistry.
       Examples:
1. NO2-Group deactivates the ring, so chlorine goes to the meta position.
                                      NO 2                        NO 2

                                                  Cl 2/Fe

                                                                             Cl
2. Iso-propyl group activates the ring, NO2-group goes to the ortho- and para-positions.


                                                                                         NO 2
                                 HNO 3
                                H2SO4

                                                         NO 2



                                                  PHENOL
Nomenclature
       Phenols are compounds containing an –OH group attached directly to an aromatic ring.
Phenols are usually named by common system or as derivatives of the parent phenol (C6H5OH).
                    OH               OH                  OH                  OH                  OH
                                               CH 3              OH


                                                                                    OH
                                                                                                 OH
                phenol         o-cresol               catechol             resorcinol           quinol

Methods of preparations
           1. From chlorobenzene (Dow process). This involved the hydrolysis of chlorobenzene
               with aqueous NaOH at high temperature and pressure followed by treatment with
               dilute HCl.
                                Cl                               ONa                        OH

                                           NaOH aq                            H+/H2O

                                      350oC, 150 atm


                                                                                                         32
                                Bioorganic chemistry for Medicine students


           2. From cumene process. The cumene process accounts for 80% of the total world
                production of phenol.

                                                           OOH
                                  O2                                  H+/H2O           OH       O




           3. From sodium benzenesulphonate. This involved fusion of sodium benzenesulphonate
                with solid NaOH at 300ºC followed by treatment with dilute HCl.
                                                                                 ONa                OH
                     SO 3H NaOH                   SO 3Na     NaOH                      H+/H2O

                                                             toC




Chemical properties
       The reaction of phenol are the reaction of the –OH group and the benzene ring.
Reaction of –OH group
       Formation of salts.
       Phenol is acidic. It reacts with sodium hydroxide or sodium metal to form salts.
                                        OH                                 ONa
                                             + NaOH


                                                           sodium phenoxide

       Formation of esters.
       Phenol reacts with acid chlorides (or acid anhydrides) in aqueous alkali solution to give
phenyl ester.
                                                                 Cl
                          OH                           ONa                        O        O
                                                             R        O
                           + NaOH
                                                                                       R

       Formation of ethers.
       Phenol reacts with alkyl halide in alkali solution to form phenyl ether.
                           OH                          ONa                         O R
                                                                   RHal
                            + NaOH


       Reaction with PCl5 or PBr5
       Phenol reacts with PCl5 or PBr5 to yield chloro- or bromobenzene.
                                             OH                           Cl
                                              + PCl5


Reaction of benzene ring
                                                                                                     33
                                Bioorganic chemistry for Medicine students
       Phenol undergoes electrophilic substitution reactions much more readily as compared to
benzene ring. Remember: OH-group is ortho- para-directing substituent.
       Halogenation.
       Phenol reacts with bromine water to give precipitate of 2,4,6-tribromophenol. Chlorine
reacts in the same way.
                                                                  Br
                                       OH                              OH
                                        + Br 2                              + HBr
                                                     Br                Br

       Nitration
       Phenol reacts with dilute nitric acid to form a mixture of o- and p-nitrophenol.
                               OH                             OH                       OH
                                + HNO 3
                                                              NO 2 O2N

       Sulphonation
       When phenol is treated with concentrated sulphuric acid at 20ºC, o-phenolsulphonic acid is
the main product. At 100ºC, p-phenolsulphonic acid is the main product.
                                                 H2SO 4                     OH

                                                 20oC
                                      OH                                    SO 3H

                                                                            OH
                                                 H2SO 4
                                                 100oC
                                                          HO 3S



                                                 ANILINE
Methods of preparations
          1. Reduction of nitro compounds. This is a very convenient and most widely used
              method of preparing aromatic amines. The reduction is carried out with a) H2 in the
              presence of Ni, Pd or Pt as catalyst; b) Sn or Fe and HCl; c) Lithium aluminium
              hydride.
                                                 O
                                             N+                                     NH 2
                                                     O–     H2/Ni



          2. Ammonolysis of Aryl chlorides. Aniline is prepared by treating chlorobenzene with
              ammonia in the presence of copper salts at high temperature and pressure.



                                                                                               34
                               Bioorganic chemistry for Medicine students
                                             Cl                                               NH 2
                                                   NH 3, CuCl 2
                                                                  ,p

Chemical properties
       The reaction of aniline are the reaction of the –NH2 group and the benzene ring.
Reaction of –NH2 group
       Salt formation
       Being basic, aniline form crystalline salts with strong mineral acids such as HCl or H2SO4.

                                          NH 2                              NH 3
                                                  HCl
                                                                                     Cl



       Alkylation
       Aniline reacts with alkyl halides to form 2o amine and 3o amines.
                                    NH 2                                    H
                                                                            N
                                      + RHal                                    R
                                                                                      + HHal


       Acylation
       With acid halides or anhydrides, aniline forms N-aryl amides.
                               NH 2         O                                   H
                                                                                N         O
                                      R                                                   + HHal
                                                Hal                                  R

       Reaction with nitrous acid
       Aniline undergoes diazotization to give diazonium salts.

                                  NH 2                                          N N
                                           NaNO 2+HCl
                                                                                              Cl
                                                 0oC


Reaction of benzene ring
Remember –NH2 group is ortho- para-directing substituent.
       Halogenation
       Halogenation with bromine or with chlorine is extremely rapid. When bromine water or
chlorine water is added to anilines at room temperature, a white precipitate of 2,4,6-tribromo- or
2,4,6-trichloroaniline is immediately formed.
                                                                       Br
                                            NH 2                                NH 2
                                                      Br 2


                                                             Br                 Br

       Sulphonation
                                                                                                     35
                                       Bioorganic chemistry for Medicine students
       On heating with fuming sulphuric acid, aniline is sulphonated to form sulphanilic acid (p-
animobenzenesulphonic acid).
                                                     NH 2                       NH 2
                                                            H2SO4


                                                             HO 3S

       Nitration
       Aniline reacts with a mixture of concentrated nitric and sulphuric acids to give m-
nitroaniline.
       Why meta product? Nitric acid is a proton acid. It reacts with the amino group to form
anilinium ion, C6H5NH3+. Because of the positive charge, the –NH3+ group is meta directing.

                           NH 2                               NH 3                                     NH 2
                                  HNO 3conc.                                HNO 3conc.
                                                                     NO 3
                                  H2SO 4 conc.                              H2SO 4 conc.

                                                                                               NO 2

       p-Nitro aniline can be obtained by first protecting the –NH2 group by acylation.
                                        H                                              H
         NH 2                           N        O                                     N   O                  NH 2
                CH 3COCl                              HNO 3conc.                                H+/H2O
                                                      H2SO4 conc.
                                                                     O2N                              O2N



                NUCLEOPHILIC SUBSTITUTION IN AROMATIC COMPOUNDS
       It is known that in aryl halides and benzenesulphonic acid the functional groups can be
substituted by nucleophilic species. The carbon which is adjacent to the functional group has partial
positive charge, so it can be attacked by a nucleophile. But in comparison with S N1 and SN2
reactions these substitutions require rather rigid conditions, usually they occur under heating and
increased pressure.
                                                 Cl                               OH
                                                        NaOH aq
                                                     350oC, 150 atm.

                                                 SO3H                             OH
                                                            NaOH
                                                             fuse


       If an aryl halide contains electron-withdrawing groups (usually it is nitro group) in ortho-
and para-positions, the halogen undergoes displacement. In this case reactions proceeds less rigid
and the more electron-withdrawing groups are on the ring the more rapidly reactions occur.




                                                                                                                36
      Bioorganic chemistry for Medicine students
          Cl                              OH

                        15% NaOH
                         150oC

          NO 2                           NO 2

         Cl                             OH
                 NO 2                            NO 2
                        Na2CO3 aq
                         130oC

         NO 2                           NO 2

          Cl                             OH
O2N              NO 2             O2N              NO 2
                         H2O
                        boiling

          NO 2                            NO 2




                                                          37
                                Bioorganic chemistry for Medicine students


                                                  Lecture 7
Alkyl and aryl halides
       The halogen atom of an alkyl halide is attached to an sp3 –hybridized carbon. The
arrangement of the groups around the carbon atom, therefore is generally tetrahedral. Because
halogen atoms are more electronegative than carbon, the C-Hal bond is polarized, the carbon atom
bears a partial positive charge, the Hal atom – a partial negative charge.
       In the laboratory and industry, alkyl halides are used as solvents and the starting material for
the synthesis of many compounds.
       Compounds in which a halogen atom is bonded to an sp2-hybridized carbon are called
vinylic halides, or, in the case of aromatic compounds – aryl halides.
Nomenclature
       Alkyl halides are named in two ways.
       1. Common system
       In this system the alkyl group attached to the halogen atom is named first. This is then
       followed by the appropriate word chloride, bromide and so on.
                                                                                    Br

                             H3C Cl                H3C      Br             H3C           CH 3
                         methyl chloride          ethyl bromide           isopropyl bromide

       2. IUPAC system
       The IUPAC names are obtained by using the following rules:
               Select the longest carbon chain containing the halogen atom and the alkyl halide as
                a derivative of the corresponding hydrocarbon.
               Number the chain so as to give the carbon atom carrying the halogen atom the
                lowest possible number.
               Indicate the position of the halogen atom by a number and by the fluoro-, chloro-,
                bromo-, or iodo-.
               Name other substituents and indicate their positions by number.
                                                                                    Br
                                        Br                        I

                             Bromoethane          1-Iodo-3-methylbutane    2-bromopropane

Methods of preparation
       1. Halogenation of alkanes. Alkanes react with Br2 or Cl2 in the presence of UV light or at
           high temperature (400ºC) to give alkyl halides along with polyhalogen derivatives.
                                       Cl2/ toC
                                CH 4               CH 3Cl + CH 2Cl 2 + CHCl   3   + CCl 4

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                                    Bioorganic chemistry for Medicine students
       This method is not used in the laboratory because of the difficulty of separating the
       products.
       2. Addition of halogen acids to alkenes. Halogen acids (HCl, HBr) add to alkenes to yield
              alkyl halides. The mode of addition follows Markovnikov rule, except for the addition of
              HBr in the presence of peroxides.
                                                                               Br
                                         R          + HBr
                                                                         R

                                                                 R2O2
                                         R            + HBr
                                                                         R          Br
       3. Action of halogen acid on alcohols. Alcohols react with HBr or HI to produce alkyl
              halides. Alkyl chloride are obtained by the action of dry HCl in the presence of zinc
              chloride catalyst.
                                         OH                                         Br     + H 2O
                                              + HBr


                                                          ZnCl 2
                                              + HCl                                         + H 2O
                                    OH                                         Cl

       4. Action of phosphorus halides on alcohols. Alcohols react with phosphorus halides (PX5,
              PX3) to give alkyl halides.
                                    OH                                        Br     + POBr 3 + HBr
                                          + PBr 5



                                         + PCl5                                          + POCl3 + HCl
                               OH                                        Cl

       5. Halogen exchange reaction. This reaction is particularly suitable for preparing alkyl
              iodides. The alkyl bromides or chlorides is heated with a concentrated solution of
              sodium iodide in acetone.
                                                              acetone                I
                                         Br                                               + NaBr
                                               + NaI

Physical properties of organic halides
       Most alkyl and aryl halides have very low solubility in water. Dichloromethane (methylene
chloride), trichloromethane (chloroform) and tetrachloromethane (carbon tetrachloride) are often
used as solvents for non-polar and moderately polar organic compounds. Many chloroalkanes
including chloroform have a cumulative toxicity and are carcinogenic, and should be used with
great care.
Chemical properties
       Alkyl halides are very reactive compounds. They undergo substitution, elimination and
reduction reactions. Alkyl halides can also react with metals to form organometallic compounds.
                                                                                                         39
                                  Bioorganic chemistry for Medicine students
Nucleophilic substitution reactions
       There are many reactions of the general type shown under.
                                 Nu   +    R      Hal           R     Nu      +      Hal-
                          nucleophile      alkyl halide            product        halide ion
                                             substrate

       In this type of reactions, a nucleophile, a species with unshared electron pair, reacts with an
alkyl halide (called substrate) by replacing the halogen substituent. A substitution reaction takes
place and the halogen substituent, called the leaving group, departs as a halide ion. Because the
substitution reaction is initiated by a nucleophile, the reaction is called nucleophilic substitution
reaction.
Two possible mechanisms of SN reactions
      SN1 (unimolecular nucleophilic substitution)
       In the case of tertiary alkyl halides (and ,under some conditions, in the case of secondary
ones) the reaction involves two steps and proceeds according to the following scheme
       Step 1. The alkyl halides ionizes to give a planar carbonium ion. The carbonium ion is
planar because the central positively charged carbon atom is sp2 hybridized.

                                          Hal                                + Hal


       Step 2. the nuclephile can attack the planar carbonium ion from either side to give the
product.

                                                            O                               OH
                                                                       -H

                           H2O

      SN2 (bimolecular nucleophilic substitution)
       In the case of primary (and often secondary) alkyl halides.
       In this mechanism, the attack of the nucleophile and the ejection of the halide ion takes place
   simultaneously. The reactants on their way to products pass through the transition state where
   the C-Nu bond is half-formed and the C-Hal bond is half-broken.

                                                         
                            Hal                  HO       Hal                               OH   + Hal

             HO
                                                transition state

                             The unreactivity of Vinylic and aryl halides
       Vinylic and aryl halides are usually unreactive in SN reactions. Vinylic and aryl carbonium
ions are highly unstable and do not form readily. This explains their unreactivity in S N1 reactions.
The C-Hal bond in these compounds is stronger, than in the case of alkyl halides and the electrons
                                                                                                         40
                                     Bioorganic chemistry for Medicine students
of the double bond or phenyl ring repel the approach of a nucleophile from the back side. These
factors explain the unreactivity of a vinylic or phenyl halide in an SN2 reaction.
         Some of the important nucleophilic substitution reactions of alkyl halides are described
below:
         Reaction with aqueous KOH or NaOH
         Alkyl halides react with aqueous potassium or aodium hydroxide to form alcohols. The
halogen atom is substituted by OH group.
                                                        KOH/H2O
                                               Br                            OH

         In this case the mechanism is SN2 since it is a primary alkyl halides. The scheme of it is
below.

                                                  H H
                                                     
                      H       Br                HO    Br                     H         OH      + Br
                          H                                                      H
              HO
                                             transition state

         Reaction with ammonia and amines
         When an alkyl halide react with ammonia or amines alkylation of the later takes place.
                                      +            Cl                                  + HCl
                              NH 2                                       N
                                                                         H
         Think about the mechanism of this reaction.
         Reaction with sodium cyanide
         Alkyl halides react sodium cyanide to give nitriles.
                                           + NaCN                                    + NaBr
                                   Br                                    CN
         Reaction with KSH
         Alkyl halides react with potassium hydrosulphite to form thiols.

                                           + KSH                                      + KBr
                                      Br                                     SH

                                                   Dehydrohalogenation
       A widely used method for synthesizing alkenes is the elimination of HX from adjacent
atoms of an alkyl halide. Heating the alkyl halide with a strong base causes the reaction to
take place. Remember: here you should use Saytzeff Rule.
                                                        KOH /alc.
                                               Br

         Grignard reagents
         Organomagnesium halides were discovered by the French chemist Victor Grignard in 1900
and are called Grignard reagents in his honor. These compounds find a wide use in organic
synthesis.
                                                                                                      41
                              Bioorganic chemistry for Medicine students
       Grignard reagents are usually prepared by the reaction of an organic halide and magnesium
metal (turnings) in ether.

                                                Mg
                                       Br     ether
                                                                   MgBr




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                                Bioorganic chemistry for Medicine students


                                                 Lecture 8
                                                 Alcohols
       Alcohols are compounds whose molecules have a hydroxyl group attached to a saturated
carbon atom. The saturated carbon atom may be that of a simple alkyl group or alkenyl and alkynyl
group or benzylic group.
Nomenclature
       Alcohol can be named by two systems:
   1. Common system.
    In this system alcohols are named as alkyl alcohol. The alkyl group attached to the –OH group
   is named and „alcohol‟ is added as a separate word.

                                                              OH
                                       OH                                     OH
                            tert-butyl alcohol   allyl alcohol         ethyl alcohol

   2. IUPAC system
   In this system alcohols are named as alkanols. The IUPAC rules are:
              Select the longest chain containing the OH group.
              Change the name of the alkane corresponding to this chain by dropping the ending –
               e ad adding the ending –ol.
              Number the chain so as to give the carbon atom carrying the OH group the lowest
               possible number. The position of the OH group is indicated by this number.
              Indicate the positions of other substituents by number.
                                                 OH              OH



                                         2-propanol           2-methyl-2-butanol

Some representatives
       Methanol
       At one time, most methanol was produced by the destructive distillation of wood (heating
wood to a high temperature in the absence of air). Today most methanol is prepared by the catalytic
hydrogenation of carbon monoxide. This reaction takes place under high pressure and at a
temperature of 300-400 C.
                                                      400 C
                               CO +2H2                                CH3OH
                                                 200 atm
                                                 ZnO-Cr2O3

       Ethanol



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                                  Bioorganic chemistry for Medicine students
         Ethanol can be made by the fermentation of sugars, and it‟s the alcohol of all alcoholic
beverages. Fermentation is usually made by adding yeast to a mixture of sugars and water.
         Ethanol is an important industrial chemical. Most ethanol for industrial purposes is produced
by acid-catalyzed hydration of ethene.
Methods of preparation
         Alcohols are prepared by the following methods:
   1. Hydrolysis of alkyl halides. Alkyl halides react with aqueous potassium or sodium
         hydroxide to give alcohols.
                                               Cl     KOH/H2O              OH


   2. Hydration of alkenes. Alkenes react with water in the presence of mineral acid (usually it is
         sulphuric acid). Remember: in this case you should use Markovnikov rule.
                                                                     HO
                                                             H
                                                    + H2O

   It is not possible to obtain primary alcohols by this method (ethyl alcohol is only exception).
   3. Addition of Grignard reagent to aldehydes and ketones. Grignard reagents react with
         aldehydes and ketones to form an addition compound which on hydrolysis with dilute acid
         to give the corresponding alcohols.

                             O                                OMgCl                 OH
                                                                          H2O/H
                       R C        + R"MgCl                  R C R'                R Ñ R'
                             R'                               R"                    R"
   Primary alcohols are obtained by treating a Grignard reagent with formaldehyde.
   Secondary alcohols are obtained by treating a Grignard reagent with aldehydes other than
   formaldehyde.
   Tertiary alcohols are obtained by treating Grignard reagents with ketones.
Chemical properties
         Alcohols are very reactive compounds. They are attacked by polar or ionic reagents. This is
because:
   1. The C-O and O-H bonds of alcohols are polar since oxygen is highly electronegative.
   2. The oxygen atom of alcohols is an electron-rich centre because it has two unshared pairs if
         electrons.
         Reaction with active metals
         Polarization of the OH bond makes the hydrogen partially positive and explains why
alcohols are week acids. Alkyl alcohols are acids weaker, than water, while phenols are stronger
acids.


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                                       Bioorganic chemistry for Medicine students
         Alcohols do not react with sodium (potassium) hydroxide, but easily react with metal
sodium to form sodium alkoxides.

                                           OH + Na                                 ONa + H      2

         tertiary alcohols are less acidic than secondary alcohols. The secondary alcohols are less
acidic than primary alcohols. This is because of the +I effect of alkyl groups. Alkyl groups will
reduce the polarization of the O-H bond.
         Reaction with phosphorus halides
         Alcohols react with phosphorus pentahalides and phosphorus trihalides to form alkyl
halides.

                                OH + PCl          5                             Cl + POCl       + HCl
                                                                                            3

         Reaction with thionyl chloride
         Alcohols react with thionyl chloride to give alkyl halides.

                                OH + SOCl             2                             Cl + SO          + HCl
                                                                                                 2

         Reaction with hydrogen halides
         Alcohol react with hydrogen halides to form alkyl halides. In generally, tertiary alcohols
react rapidly with hydrogen halides; secondary alcohols react somewhat slower; and primary
alcohols even more slowly. The order of reactivity of hydrogen halides is HI > HBr > HCl. HCl
reacts only in the presence of a catalyst (anhydrous ZnCl2).

                                       OH + HBr                                       Br + H 2O

                                                               ZnCl 2
                                            OH + HCl                                Cl+ H 2O

         Mechanism: Primary alcohols react with hydrogen halides by an S N2 mechanism. The
mechanism of the reaction between ethyl alcohol (1º alcohol) and hydrogen bromide is described
below:
         Step 1. Proptonation of ethyl alcohol.

                                             OH + H                                         H
                                                                                       O
                                                                                       H
                                   -
         Step 2. Nucleophile (Br ) attacks the carbon atom carrying the proponated hydroxyl group to
form ethyl bromide.
                                                                            H
                                       H
                  Br   +       O                          Br            O                            Br + H2O
                               H                                            H

         Tertiary react with hydrogen halides by SN1 mechanism (see lecture 7).
         Reactions with sulphuric acid
         Alcohols react with sulphuric acid to give different products at different temperatures.
                                                                                                                45
                                 Bioorganic chemistry for Medicine students
       Reaction at 0-20ºC
       When alcohol is treated with concentrated sulphuric acid at 0-20ºC, hydrogen sulphate is
formed.
                                              H2SO4 conc.
                                         OH                       OSO 3H
                                                 0oC
       Reaction at 70-140ºC
       When alcohol (it is only in case of primary alcohols) is treated with concentrated sulputic
acid at 70-140ºC, ether is obtained.
                                              H2SO4 conc.
                                         OH                       O
                                                 140oC

       Reaction at 150-180ºC
       When alcohol is treated with concentrated sulphuric acid at 150-180ºC, elimination of
molecule of water occurs. Remember: Use Saytzeff rule to write the correct product.
                                                    H2SO4 conc.
                                               OH
                                                       170oC
       Reaction with carbonic acids
       Alcohols react with carbonic acids in the presence of small amount of mineral acid ( usually
it is sulphuric acid) to form ester. The reaction is reversible and can be shifted in the forward
direction by removing water as soon as possible. The reaction between alcohol and carbonic acid to
form eater is called esterification.
                           O                                          O
                                                       H
                                    +                                            + H 2O
                     H3C       OH        HO                    H3C        O


       Remember: OH Group leaves the carbonic acid not the alcohol.
       Reaction with Grignard reagents
       Alcohols react with Grignard reagents to yield alkanes.
                               OH + CH 3MgBr                              OMgBr + CH   4


       Reduction
       Alcohols undergo reduction with concentrated hydriodic acid and red phosphorus to produce
alkanes.
                                       OH + HI                        + I 2 + H 2O

       Oxidation
       Alcohols can be oxidized. The nature of the products depends on the type of alcohol and the
conditions of the reaction. Most widely used oxidizing agents are KMnO4+H2SO4 or



                                                                                                 46
                                Bioorganic chemistry for Medicine students
K2Cr2O7+H2SO4. Primary are alcohols first oxidized to aldehydes and then to acids. Secondary
alcohols are oxidized to ketones.
                                                                            O
                                                     KMnO 4/H2SO 4
                                              OH           25oC                 H
                                         OH             KMnO 4/H2SO 4       O

                                                           25oC

       Reaction with the hot copper (dehydrogenation)
       Different types of alcohols give different products when their vapors are passed over copper
gauze at 300ºC. Primary alcohols lose hydrogen and give aldehydes. Secondary alcohols give
ketones. Tertiary alcohols lose molecule of water to yield alkenes.
                                                                            O
                                                          Cu
                                              OH         300oC                  H
                                         OH                                 O
                                                           Cu

                                                          300oC

                                              OH            Cu

                                                           300oC

                                              Polyhydric alcohols
       Compounds which contains more than one –OH group are called polyhydric alcohols or
polyols.
Nomenclature
       Diols and triols have both common and IUPAC names. The IUPAC names are obtained by
adding the suffix diol or triol to the name of the parent alkane. Numbers are used to indicate the
positions of the -OH groups.


                                                          OH                 OH
                      HO                      HO                  OH                  OH
                                    OH
                        1,2-ethanediol         1,2,3-propanetriol           1,2-propanediol
                        ethylene glycol            glycerol                  Propelene glycol


Methods of preparation for ethylene glycol
   1. By oxidation of ethylene with cold potassium permanganate solution.
                                                   KMnO 4         HO
                                                                                OH
                                                   H2O/0oC

   2. By hydrolysis of 1,2-dibromoethane with aqueous solution of KOH.
                                                        KOH/H2O
                                    Br                                 HO
                                                   Br                                OH

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                                Bioorganic chemistry for Medicine students
   3. By hydrolysis of ethylene oxide with water at 200ºC under pressure or with dilute sulphuric
       acid.

                                                 H2O/H      HO
                                     O                                  OH

Methods of preparation for glycerol
   1. From fats and oils. Natural oil and fats are triasters of glycerol and long-chain carboxylic
       acids (mainly palmitic, stearic and oleic acids).
                                         RO 2C                         OH
                                                       NaOH
                                    RO 2C                                   OH


                                         RO 2C                         OH

   2. From propene by the catalytic cracking of petroleum.
                                                      Cl2/600oC
                                                                             Cl

                                                      NaOH
                                               Cl                            OH

                                                                       OH
                                                       HOCl
                                                 OH             Cl               OH

                                         OH            NaOH             OH
                               Cl                OH             HO                OH

Chemical properties
       The chemical properties of ethylene glycol and glycerol are similar to the chemical
properties of alcohols. But they can give reactions in which one or more OH groups are involved.
       Reaction with sodium
       Ethylene glycol and glycerol react with sodium to form mono-, di- and in case of glycerol
trialkoxide.
                                    Na                            Na
                   HO                     NaO                           NaO
                              OH                           OH                          ONa

       Reaction with hydroxides
       Since polyols have more than one OH group, they are more acidic than alcohols. Therefore
ethylene glycol and glycerol can react with sodium or potassium hydroxide.
                                                    NaOH
                               HO                          NaO
                                              OH                        ONa

                               HO                          NaO

       Reaction with copper hydroxide




                                                                                                   48
                                        Bioorganic chemistry for Medicine students
       When ethylene glycol or glycerol is treated with copper hydroxide, the complex between the
polyol and copper hydroxide is formed. The complex has intense blue color. By this reaction you
can distinguish the presence of a polyol.
                                                                             H
                                                      Cu(OH) 2
                                   HO                                O   O
                                                OH                    Cu
                                                                     O   O
                                                                         H       H
                                        OH                               O   O
                                                      Cu(OH) 2
                                                                          Cu
                           HO                  OH
                                                                         O   O
                                                                                              OH
                                                                             H
                                                                   OH
       Reaction with phosphorus pentahalides
       Polyols react with PCl5 or PBr5 to give mono- or poly-halides.
             OH                                OH                                OH                             Cl
                           PCl 5                           PCl 5                              PCl 5
     HO               OH            Cl                OH            Cl                   Cl            Cl            Cl

       Reaction with carbonic acids
       Polyols react with carbonic acids in the presence of mineral acid to form esters.

                                                 O                                                 O
                                                            H
                      HO                                                             O
                                   OH +              OH                                       O
                                                                             O
       Fats. Natural fats and oils are the trimesters of glycerol with long-chained carboxylic acids
(12 to 20 carbons).
                                                                         C17H35
                                                                                         O
             HO            OH                  O           H                     O                     O
                             +      HO                                               O         O
                                               C17H35              C17H35                              C17H35
               HO
                                                                                     O




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                                  Bioorganic chemistry for Medicine students
                                                 Lecture 9
                                                    Amines
       Colombian poison dart frogs are tiny, beautiful and deadly. They produce a poison called
histrionicotoxin, which is an amine that causes paralysis. A key feature of the structure of
histrionicotoxin is the presence of secondary amino group.
                                                     H

                                               HN
                                              OH




       Amines can be found very often in nature. These compounds exhibit a great variety of
biological activity.
Nomenclature
       Amines can be named in two ways
       In common nomenclature most primary amines are named as alkylamines. Amines are
classified as being primary, secondary or tertiary on the basis of the number of organic groups
attached to the nitrogen.
                                              Primary amines
                                                    NH 2
                                  NH 2                                         NH 2

                             methylamine       iso-propylamine     butylamine

                                            Secondary amines

                                                    NH
                                  NH                                       NH

                       dimethylamine      isopropylmethylamine       butylpropylamine

                                              Tertiary amines

                                                N
                              N                                                N

                 trimethylamine    isopropylmethylpropylamine        butylmrthylpropylamine

Basicity of amines
       Amines are relatively weak bases. They are stronger bases than water, but far weaker bases
than hydroxide ions. When we examine the basicities of alkyl amines, we see, that they are stronger
bases, than ammonia. We can account for this on the bases of the electron-releasing ability of an

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                                Bioorganic chemistry for Medicine students
alkyl group. An alkyl group release electrons and it stabilizes the alkylaminium ion that results from
the acid-base reaction by dispersing its positive charge.

                                     H
                                              + H 2O                    R-NH 4 + HO
                                R N
                                         H
        The explanation is supported by measurements showing that the basicities of the alkyl
substituted amines increase with increasing alkyl substitution.
        Aromatic amines exhibit lower basicity than alkyl substituted amines. Electron accepting
groups in the aromatic ring decrease the basicity, electron donating increase it.
Methods of preparation
   1. Reaction of alkyl halides with ammonia.
                                         I + NH 3                        NH 2 + HI
                                                                          H
                                         I +          NH 2                N        + HI

                                          I           H
                                              +       N                   N       + HI



                                              +           I
                                      N                                       N          I


   2. Reduction of nitro compounds. Primary amines can be obtained by reduction of nitroalkanes
        with H2/Pt or lithium aluminum hydride.
                                                              H2/Pt
                                                  NO 2                            NH 2

   3.    Reduction of oximes, nitriles with lithium aluminum hydride.
                                                              LiAlH 4
                                                  N                               NH 2
                                                  OH

                                                              LiAlH 4
                                                      N                              NH 2



Chemical properties
        The main reactions of amines are due to the presence of lone pair of electrons on nitrogen.
This lone pair of electrons is available for donating to electron-seeking reagents. Amines are
nucleophilic reagents.
        Salt formation
        Amines are basic compounds. They react with mineral acids to yield salts.

                                   NH 2 + HCl                                     NH 3
                                                                                             Cl


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                                     Bioorganic chemistry for Medicine students
       Reaction with alkyl halides
       When amine is treated with an alkyl halide, hydrogen atoms of the N atom are replaced by
alkyl group. In the final step, the tertiary amine adds one molecule of the alkyl halide to form a
quaternary ammonia salt.

                                          I           H              I                           I
                            NH 2                      N                          N




                                                      N          I


       Reaction with acid chlorides (acylation)
       Primary and secondary amines react with chlorides to give N-substituted amides.
                                                  O                      O
                                          +                                              + HCl
                                   NH 2               Cl                     N
                                                                             H

       Reaction with nitrous acid
       Nitrous acid is an unstable substance and is therefore prepared in situ by the reaction of
sodium nitrite with dilute HCl at 0ºC. Primary, secondary and tertiary amines react with nitrous acid
differently.
                  Primary amines react with nitrous acid to form alcohols and nitrogen gas.
                                                           NaNO 2+ HCl
                                                  NH 2                               OH + N 2
                                                               0oC

                  Secondary amines react with nitrous acid to form N-nitrosoamines which water-
                   insoluble yellow oils.
                                                              NaNO 2+ HCl
                                                                                         N
                                                  N              0oC
                                                  H                                      N
                                                                                     O

                  Tertiary amines react with nitrous acid to form trialkylammonium nitrite salts
                   which are soluble in water.

                                                           NaNO 2+ HCl               H
                                                                                     N       NO 2
                                              N               0oC



       This reaction is used as basis of a test to distinguish between primary, secondary and tertiary
amines.
       Reaction with benzenesulphonyl chloride




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                                   Bioorganic chemistry for Medicine students
       Primary and secondary amines react with benzenesulphonyl chloride to yield sulphoamides.
Tertiary amines can‟t react with benzenesulphonyl chloride since they do not have a replaceable
hydrogen attached to the N atom.


                                     +
                                                NH 2                                  N
                                                                                 S
                                                                                 O2
                            SO 2
                       Cl

       Among sulphoamides there are many medicines, for example sulphadiazine or
Sulfanilamide.
                                                             NH2
                                      N
                                          O
                               N            S
                                          N
                                          H O    sulphadiazine


                                                       O
                             H 2N                  S       NH2
                                                                 Sulfanilamide
                                                       O




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                               Bioorganic chemistry for Medicine students
                                               Lecture 10
                                       Aldehydes and ketones
       Both aldehydes and ketones contain a carbon-oxygen double bond (>C=O). This unit is
called carbonyl group. Collectively these compounds are called carbonyl compounds. In
aldehydes, the carbonyl carbon is boned to one hydrogen and one alkyl group. Formaldehyde,
HCHO, in which the carbonyl carbon is boned to two hydrogen atoms is an exception. In ketones,
the carbonyl carbon is bonded to two alkyl groups. These alkyl groups may be different or same
Nomenclature
      Aldehydes
       There are two systems of naming aldehydes.
           1. Common system
              Common names for aldehydes are obtained from the names of the corresponding
           carboxylic acids. The aldehyde name is obtained by replacing the ending –ic acid of the
           acid name with –aldehyde.
                                                O                     O
                                           H                      H
                                                OH                      H
                                        formic acid              formaldehyde
                                              O                      O

                                       H3C                    H3C
                                               OH                     H
                                     acetic acid              acetaldehyde

           2. IUPAC system
           IUPAC names for aldehydes are obtained by replacing the ending –e of the
           corresponding alkane with –al. The carbonyl carbon is assigned number 1.
                                       O                     O                    O
                                 H                    H3C
                                      H                      H                 H
                                methanal               ethanal              propanal

      Ketones
       There are two systems of naming ketones
           1. Common system
              Common names of ketones are obtained by simply naming the two alkyl groups
           attached to the carbonyl group and adding the word ketone.
                                                O                     O



                                     dimethyl ketone        ethyl methyl ketone
                                        acetone



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                              Bioorganic chemistry for Medicine students


          2. IUPAC system
             IUPAC names of ketones are obtained by replacing the ending –e of the
          corresponding alkanes with –one. The chain is then numbered to give the carbonyl
          carbon the lowest number. This number is then used to designate the position of the
          carbonyl group.
                                 O                       O                    O



                             propanone              butanone           2-pentanone

Methods of preparation
          1. Oxidation of alcohols. Aldehydes and ketones can be prepared by the controlled
             oxidation of primary and secondary alcohols using an acidified solution of potassium
             dichromate or permanganate.
                                                                       O
                                                    KMnO 4/H2SO 4
                                               OH        25oC                 H
                                          OH        KMnO 4/H2SO 4         O

                                                         25oC

          2. Catalytic dehydrogenation of alcohols. Aldehydes may be prepared by passing the
             vapours of primary alcohols over a copper catalyst heated to 300 C.
                                                                       O
                                                        Cu
                                               OH       300oC                 H
                                          OH                              O
                                                         Cu

                                                        300oC

          3. Hydration of alkynes. Hydration of acetylene gives acetaldehyde. Hydration of
             alkynes other than acetylene, yields ketones.
                                                                           O
                                                          H2O/H +
                                      H             H
                                                             Hg 2+             H
                                                         H2O/H    +           O
                                      H3C
                                                          Hg 2+

          4. Pyrolysis of calcium salts of acids. This method is only for ketones.


                                               O

                                               O
                                          Ca
                                               O
                                                                      O

                                               O                                              55
                                   Bioorganic chemistry for Medicine students


Chemical properties
       Nucleophilic addition reactions
       The carbonyl group of aldehydes and ketones is a highly polar group. It may be represented
as:
                                                                                  
                                      O                      O                    O
                                                                             


       The positively charged carbon atom is readily attacked by electron-rich nucleophiles.
       Aldehydes and ketones undergo nucleophilic addition reactions by the following general
mechanism.
       Step 1
       Nucleophile attacks the positively charged carbonyl carbon to form a new bond. As the new
bond is formed, π-bond between the carbon and oxygen us broken. The electron pair goes to
oxygen, which acquires a negative charge.
                                                                      Nu
                                                O
                              Nu                                                O



       Step 2
       The electrophile attacks the negatively charged oxygen to form the addition product.
                               Nu                                  Nu
                                          O      +H                          O
                                                                             H
                                                                 addition product

       Addition of sodium bisulphate
       Aldehydes and methyl ketones react with a saturated water solution of NaHSO3 to form
solid addition compounds.
                                       O                                 OH
                                               + NaHSO   3

                                                                         SO3Na

       Addition of HCN
       Aldehydes and ketones can react with hydrogen cyanide to yield cyanohydrins. The
reaction is carried out in the presence of a basic catalyst.
                                           O                                 OH
                                                    + HCN                         H
                                           H                                 CN

       The mechanism involves three steps:
       Step 1
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                                  Bioorganic chemistry for Medicine students
         The base removes a proton from hydrogen cyanide to produce cyanide ions.

                                        HCN + OH             H2O + CN

         Step 2
         The cyanide ion attacks the carbonyl carbon to form an anion.
                                       O                              NC
                                                CN                              O
                                       H

         Step 3
         The proton from the solvent (usually water) combines with the anion to give cyanohydrin.
                                  NC                               NC
                                            O   +H                          O
                                                                                H

         Addition of Grignard Reagents
         Aldehydes and ketones react with Grignard reagents to give an addition product which can
be hydrolyzed with dilute acid to yield an alcohol. The reaction provides a convenient way of
preparing alcohols that contain a large carbon chain than the starting materials. Formaldehyde reacts
with Grignard reagents to produce primary alcohols. Other aldehydes give secondary alcohols.
Ketones react with Grignard reagents to produce tertiary alcohol (see lecture 8).

                      O                                       OMgBr                     OH
                                                                            H2O/H
                             + CH3MgBr                   H
                  H
                                                              CH 3

         Addition reactions followed by loss of water
         Addition of alcohols
         Alcohols react with aldehydes in the presence of anhydrous HCl to form unstable addition
products – hemiacetals. These hemiacetals react further with alcohol to form stable compounds
known as acetals.
                                    O                                           OCH 3
                                                             HCl
                                            + CH 3OH                  H3C           H
                            H3C
                                        H
                                                                                OCH 3

         Reactions with ammonia derivatives
         Such ammonia derivatives as amines, hydrazines, hydroxylamines react with aldehydes and
ketones to form compounds containing carbon-nitrogen double bond.
                                    O
                                            +   NH 2-R                              R
                                                                                N

                             R=H, alkyl groups, OH, NH2, NH-R

         The mechanism of the above reaction involves the following steps:
Step 1
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       Ammonia derivatives behave as nucleophilic reagents since they have an unshared electron-
pair on nitrogen. They add to the carbonyl group in aldehydes and ketones.

                           O                                       O                              OH
                                                                             proton
                                                                   C                              C
                                   + NH2-R                     H N R         transfer         H N R
                                                                   H
       Step 2
       Addition product rapidly loses a molecule of water to give the final product.
                                           OH
                                                                        N
                                           C                                R        + H 2O
                                   H N R

       Aldol condensation
       Carbonyl compounds having -hydrogens undergo self addition to form products called
aldols. The reaction is called aldol condensation.

                                                               O                         OH       O
                                O                                      OH
                                                +
                                                       H3C         H                                  H
                         H3C           H

       The reaction is reversible and involved the following steps:
       Step 1
       The enolate ion is formed.
                                                                                O
                                       O
                                                    + OH                                 + H 2O
                             H3C               H                        H2C          H

       Step 2
       The enolate ion attacks the carbonyl carbon of another un-ionized aldehyde molecule.

                                   O                           O                     O        O
                                                   +
                          H3C          H               H2C         H          H3C                     H



       Step 3
       The negative oxygen in the product accepts a proton from water to give aldol.

                               O           O                                    OH       O
                                                       + H2O                                      + OH
                       H3C                         H                   H3C                    H

       Aldols are easily dehydrated by heating or by treatment with dilute acid to form α,β-
unsaturated aldehydes.
                                           OH          O                                 O

                                H3C                        H           H3C                    H

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                                   Bioorganic chemistry for Medicine students
       Ketones containing α-hydrogen also undergo aldol condensation to form ketols.

                                         O                             OH    O
                                                    OH

                                H3C          CH 3               H3C              CH 3

       Ketols are also easily dehydrated by heating or by treatment with dilute acid to form α,β-
unsaturated ketones.
                                    OH       O                                   O

                             H3C                 CH 3             H3C                 CH 3



       Chlorination
       Under suitable conditions, chlorine will replace -hydrogens in aldehydes and ketones.
                                                  O               Cl         O
                                                         Cl 2

                                                  H                          H

       Reduction to alcohols
       Aldehydes and ketones can be reduced to alcohols by treatment with hydrogen and Ni
catalyst, LiAlH4 and some other reagents.
                                             O
                                                      LiAlH 4                    OH

                                             H
                                                                        OH
                                       O              LiAlH 4




       Oxidation of aldehydes
       Tollen’s reagent is an ammoniacal solution of silver oxide. It is obtained by adding
ammonia to a precipitate of silver oxide. When it is used to oxidize an aldehyde, the silver ion is
reduced to metallic form and the reaction is carried out in a clean test tube, deposits as a mirror (the
silver mirror). The silver mirror formed indicates the presence of an aldehyde group in a molecule.
                                         O                                  O
                                                 Ag(NH 3)2OH
                                                                                 + Ag
                                         H                                  OH

       Ferling’s solution is an alkaline solution of cupric ion complexed with sodium potassium
tartrate ions. When Ferling‟s solution is used to oxidize an aldehyde, the complex cupric ion is
reduced to cuprous oxide. The presence of the precipitate of cuprous oxide serve as an indication of
an aldehyde group in a molecule.
                                         O                                  O
                                                    Cu 2+
                                                                                 +Cu +
                                         H                                  OH
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                                    Bioorganic chemistry for Medicine students
      Haloform reaction
      Acetaldehyde and methyl ketones react rapidly with halogen in the presence of alkali to
form haloform.
                     O                                      O
                                + Br 2 + NaOH                         + CHBr   3   + H 2O + NaBr
                 R       CH 3                           R       ONa




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                                   Bioorganic chemistry for Medicine students
                                                     Lecture 11
                                                Carbonic acids
       Organic compounds which contain the carboxyl group (COOH) are called carboxylic acids.
Carboxylic acids are further classified as monocarboxylic acids, dicarboxylic acids etc according to
the number of COOH groups present. The long chain monocarboxylic acids are commonly called
fatty acids, because many of them are obtained by hydrolysis of animal fats.
                                                Nomenclature
       There are two ways of naming acids.
      Common system
       The simple acids are usually named by common system. In the common system Greek
   letters are used to indicate the position of substituents. The carbon atom adjacent to the
   carboxylic group is assigned the letter α, the next carbon on the chain β and so on.
                                                                                                    O
                                                                                 O
                 O                  O                       O
            H                                                                                       OH
                                                                                 OH
                  OH               OH                     OH
          formic acid         acetic acid           propionic acid       butyric acid        valeric acid

      IUPAC system
       In the IUPAC system the carboxylic acids are named as ALKANOIC acids. The name of an
   acid is obtained by replacing the ending -e from corresponding alkane by -oic acid.
                                                                                                    O
                                                                                 O
                 O                  O                       O
            H                                                                                       OH
                                                                                 OH
                  OH               OH                     OH
          formic acid         acetic acid           propionic acid       butyric acid        valeric acid

       For naming higher members, the longest chain containing the carboxyl group is selected.
   The number of carbon atoms in this chain gives the name of the parent alkane. The position of
   substituents is indicated by numbers. The carboxyl carbon is always given number 1, the
   carbon atom adjacent to it is given the number 2, and so on.
Methods of preparation
   1. Oxidation of primary alcohols or aldehydes. Alcohol is first oxidized to an aldehyde, and
       then, to carboxilic acid.
                                              [O]               O    [O]                O
                              R                         R                        R
                                     OH                         H                       OH

   2. Hydrolysis of nitriles or alkyl cyanides.
                                                                            O
                                                         H2O/H +
                                          R    C N                   R
                                                                            OH

   3. Hydrolysis of esters.
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                                      Bioorganic chemistry for Medicine students
                                                  O                        O
                                                         H2O/H +
                                            R                       R
                                                  OR'                      OH

    4. Reaction of Grignard reagents with CO2. The reagent reacts with CO2 to form addition
         products that can be hydrolyzed by dilute acids to carboxylic acids.
                                                                  O                               O
                                              CO 2                         H2O/H +
                              R MgHal                     R                              R
                                                                  OMgHal                          OH

Acidity of carboxylic acids
         Carboxylicacids are acidic in nature. They can donate a proton and form salts with bases.
The carboxylate ion formed by ionisation or reaction with a base is stabilized by resonance.

                                  O                           O                      O
                                                                              R
                              R                       R
                                  O                           O                      O

         Effect of substituenys on acidity
    1. Electron-releasing alkyl groups decrease the acidity. This is because the electrion-
         releasing droups increase the negative charge on the carboxylate ion and destabilize it. The
         loss of the proton becomes more difficult. as the size of the alkyl group increases, the
         acidity decreases.
                                              O                    O                         O
                                  H                       H3C
                                              OH                   OH        H 3C            OH



                                                   the acidity increases

    2. Electron-withdrawing substituents increase the acidity. This is because the electron-
         withdrawing substituents decrease the negative charge on the carboxylate ion and stabilize
         it. The loss of the proton becomes relatively easy. As the number of the electron-
         withdrawing substituents increases, the acidity increases.
                                  F           O           F           O              O
                                      C                   CH                 H2C
                                  F       F   OH          F           OH     F       OH


                                                   the acidity increases

         In comparison with mineral acids carboxylic acids are weaker.
                                                   Chemical propreties
         The main chemical reactions of carboxylic acids are described below.
         Salt formation
         Carboxylic acid react with hydroxides, carbonates, bicarbonates to form the corresponding
salts.
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                                         O                             O
                                                 NaOH
                                  H3C                         H3C
                                         OH                            ONa
                                                               sod acetate

         The carboxylic acids can be regenerated by treating these salts with dilute mineral acids.
                                           O                                        O
                                H3C                + HCl             H3C              + NaCl
                                           ONa                                      OH

         Formation of acid halides
         Carboxylic acids react with phosphorus halides or thionyl chloride (SO 2Cl) to form acid
halides.
                                      O            PCl 5                   O
                            H3C                                  H3C            + POCl3 + HCl
                                      OH                                   Cl

                                      O            SOCl 2                  O
                           H2C                               H2C                + SO 2 + HCl
                          H3C         OH                    H3C            Cl

         Formation of amides
         Carboxylic acids react with ammonia to give salts, which on heating yield amides.
                            O         NH 3                       O                                   O
                    H3C                              H3C                                       H3C
                            OH                                   O-NH 4+                             NH 2
                                                                                              acetamide
         Formation of ester
         Carboxylic acids react with alcohols in the presense of a strong acid catalyst like H 2SO4 or
HCl to form ester. The reaction is reversible and is called esterification.
                                   O                        H+                  O
                              R            + HOR'                      R                 + H 2O
                                   OH                                           OR'
                                                                       ester

         Mechanism
         The mechanism of esterification involves the following steps.
Step 1
         Protonation of carboxylic acid.
                                               O                                        OH
                                      R             + H                    R
                                               OH                                       OH

Step 2
         Attack by nucleophilic R‟OH.
                                      OH            H                                OH H
                              R                     O R'                        R            O R'
                                      OH                                             OH
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                                   Bioorganic chemistry for Medicine students
Step 3
         Hydrogen ion transfer.

                                                                        H        H
                                       OH H                                 O
                                   R           O R'                     R           O R'
                                       OH                                   OH

Step 4
         Elimination of proton and water

                          H        H
                              O                                   OH                       O
                         R         O R'                   R                           R
                                                 -H2O             OR'       H+             OR'
                              OH

         Formation of anhydrides
         Carboxylic acids undergo dehydration with phosphorous pentoxide to form acid anhydrides.
                                                                                O
                                                 O       P2O5           R
                                           R                                    O
                                                 OH                     R
                                                                                O

         Reduction
         Carboxylic acids undergo reduction with lithium aluminum hydride to give primary
alcohols.
                                                 O      LiAlH 4
                                       R                                     OH
                                                                   R
                                                 OH

         α-Halogenation
         When a carboxylic acid that contains α-hydrogen is treated with Cl2 or Br2 in the presense of
phosphorus, the α-hydrogen atoms are substituted by chlorine or bromine atoms. The reaction is
known as the Hell-Volhard-Zelinsky reaction.
                                                 O                 Br            O
                                                         Br2/P

                                       R         OH                 R            OH




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                                                        Lecture 12
                                               Hydroxy acids, keto acids
                                                    Hydroxy acids
        They are the derivatives of carboxylic acids in which one or more hydrogen atoms of the
hydrocarbon group are replaced by as many OH groups. They are referred to as α, β, γ, δ etc.,
hydroxyl acids according as the OH is bonded to α, β, γ or δ carbon of the chain. The position of
OH groups on the carbon chain are indicated by Creek letters or by numbers. Some of the important
hydroxyl acids are:
                                O                H3C            O          H3C             O

                       HO       OH                HO            OH               HO        OH
                    hydroxyacetic acid         -hydroxypropionic acid           -hydroxybutanoic acid
                      glycolic acid                lactic acid                   2-hydroxybutanoic acid


                                    H3C                 O
                                                                    3-hydroxybutanoic
                                           OH      OH

Methods of preparation
    1. By hydrolysis of cyanohydrins derived from aldehydes or ketones.
                               O                            H                               R    O
                                     HCN                                   H2O/H +
                          R                            R            CN
                               H                            OH                             HO    OH

    2. By hydrolysis of halo acids with dilute aqueous alkali.
                                           R        O       H2O/OH -         R        O

                                         Hal        OH                     HO         OH

Chemical properties
        The hydroxy acids have a carboxylic and an alcoholic group in the same molecule. they give
characteristic reactions of the both these functions. The action of heat on hydroxyl acids is of
special interest.
        Action of heat
        Hydroxy acids when heated yield a variety of products depending on the distance between
Oh and COOH groups.
    1. Alpha-hydroxy acids. α-Hydroxy acids form intermolecular cyclic diester called a lactide.
        They do so by reaction between OH of one molecule with COOH group of the second
        molecule.




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                            Bioorganic chemistry for Medicine students
                                R        O                        R
                                                                                      O
                                HO       OH                              O
                                HO           OH                                   O
                                                                O

                                             R                               R
                                    O
2. Beta-hydroxy acids. β-Hydroxy acids dehydrate by splitting out OH and H from adjacent
   carbon atoms, forming unsaturated acids.
                            R                O
                                                                R                     O
                                OH      OH
                                                                                  OH

3. Gamma and delta hydroxyl acids. These acids form interesters known as lactones. The
   COOH at one end of the molecule reacts with Oh group on the other end to form five- and
   six-membered cyclic ester, γ- and δ-lactones.
                                R
                                                  O
                                                                                       O
                           HO
                                                                     R           O
                                             OH

   Reaction involving COOH and OH groups
1. Reaction with sodium metal. They can react with sodium metal to yield salts.
                                 R       O            Na       R             O

                                HO       OH                   NaO            ONa

2. Action with PCl5. Both the OH and COOH groups are attacked by phosphorus
   pentachloride to give chloride.
                                    R        O        PCl 5      R               O

                                HO           OH                 Cl               Cl

   Reaction involving COOH group
1. Formation of salts. It react with alkalis to form salts.
                                 R       O        NaOH         R             O

                                HO       OH                   HO             ONa

2. Reaction with alcohols. Hydroxy acids react with alcohols in the presence of mineral acids
   to form esters.
                                    R    O        R'OH/H +      R            O

                                HO       OH                    HO            OR'

   Reaction involving OH group
1. Action with anhydrides. The alcoholic OH group can be acetylated with the action of
   anhydrides.

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                                 Bioorganic chemistry for Medicine students
                                      R       O (R'CO) O        R       O
                                                          2

                                     HO        OH                       O         OH
                                                                             R'
                                                                        O

                                                       Keto acids
       Organic compound which at the same time contain carboxylic and carbonyl groups are
called keto acids. They are referred to as α, β, γ, δ etc., keto acids according as the CO is bonded to
α, β, γ or δ carbon of the chain. The position of carbonyl groups on the carbon chain are indicated
by Creek letters or by numbers. Some of the important hydroxyl acids are:
                         O      O                  O        O
                                                                            H3C          O

                         H      OH            H3C           OH                   O    OH
                     formylmethanoic acid 2-oxopropanoic acid                3-oxobutanoic acid
                                             pyruvic acid

Methods of preparation
   1. Oxidation of hydroxyl acids by the action of Fenton‟s reagent (H2O2/Fe3+).
                                     HO           O H O /Fe 3+ O              O
                                                     2 2

                                         R        OH                R         OH

   2. By hydrolysis of dihalo acids with aqueous alkalis.
                                     Hal     Hal O       H2O/OH - O           O

                                         R        OH                R         OH

Chemical properties
       Reaction involving COOH group
   1. Reaction with alkalis. Keto acids react with alkalis to yield salts.
                                     O        O         NaOH        O        O


                                     R        OH                    R        ONa

   2. Reaction with alcohols. Keto acids react with alcohols in the presense of mineral acid to
       form ester.
                                     O        O                     O         O
                                                       R'OH/H +

                                     R        OH                    R         OR'

       Reaction involving CO group
   1. Reaction with HCN.
                                     O        O          HCN      HO          O

                                     R        OH                    R CN OH

   2. Reaction with ammonia derivatives.

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                                 R'
   O        O     NH -R'       N       O
                      2


   R       OH                 R        OH




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                                 Bioorganic chemistry for Medicine students
                                                 Lecture 13
                                        Amino acids and proteins
                                                 Amino acids
       Amino acids are the building blocks of the molecular structure of the important and very
complex class of compounds known proteins. As the term suugests. amino acids are bifunctional
compounds containing both an amino and a carboxylic acid group.
Nomenclature
       They are named as amino-substituted aliphatic carboxylic acids and are designated α, β, γ
etc., depending on the position of NH2 on the chain.
                       O                      O
                                                                             O                        O
                                                                                      H2N
             H2N       OH          H2N        OH             NH 2       OH            OH
          aminoacetic acid -aminopropionic acid aminopropionic acid aminobutyric acid
           glycine               alanine

       In IUPAC name of amino acids, the position of NH2 is indicated by the number of carbon to
which it attached, taking C of COOH as „1‟. Thus α-aminopropionic acid is named as 2-
aminopropionic acid.
Methods of preparation
   1. Amination of α-halo acids. α-Halo acids on treatment with aqueous ammonia give the
       respective amino acids.
                                        R        O    NH 3          R            O


                                     Hal         OH            H2N               OH

   2. Streker Synthesis. The treatment of an aldehyde with hydrogen cyanide and ammonia
       followed by hydrolysis of the aminonitrile thus formed, yields α-amino acid.
                       O                    CN                          CN       H2O/H +    R    O
                            HCN                    NH 3
                   R                R                        R
                       H                    OH                          NH 2               H2N   OH



Chemical properties
       The reaction of amino acids are those characteristic of carboxylic acids and primary amines.
in addition, they give reactions in which both NH2 and COOH groups are involved.
        Dipolar nature of amino acids-zwitterion
       The uncharged, electrically neutral molecule of an amino acid is not correct. The COOH
group being acidic will ionize in water solution. On the other hand the NH 2 group with a lone pair
of electron is a base and is capable of accepting a proton. In a neutral amino acid solution, The
COOH loses a proton and the NH2 of the same molecule picks up one.


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                                Bioorganic chemistry for Medicine students
                                     R        O           R       O


                                    H 2N             OH         H3N               O

       The resulting ion is dipolar, charged but overall electrically neutral. This is called
zwitterions. Therefore, amino acids are amphoteric. Their structure allows them to donate or accept
proton while they react with the medium in which they are dissolved, depending on pH of the
medium.
                            R       O       -            R          O                 R         O
                                                OH                          H+

                          H2N       O                H2N            OH            H3N           OH

       Reaction involving COOH group
       At the COOH group, amino acids give the usual reactions of carboxylic acids.
   1. Salts formation with bases.
                                        R            O                      R         O
                                                             NaOH

                                    H2N              OH                 H2N           ONa

   2. Ester formation in the presence of dry HCl.
                                        R            O                  +   R             O
                                                             R'OH/H

                                    H2N              OH                 H2N               OR'

   3. Reaction with PCl5.
                                        R            O                       R            O
                                                              PCl 5

                                     H2N             OH                 H2N               Cl

       Reaction involving NH2 group
       At the NH2 group. amino acids respond to all the usual reactions of primary amines.
   1. Reaction with strong acids to form salts.
                                        R            O                       R            O
                                                              HCl

                                    H2N              OH                 H3N               OH
                                                                          Cl
   2. Alkylation with alkyl halides.
                                        R            O                       R            O
                                                              R'Hal

                                    H2N              OH                     HN            OH
                                                                                 R'
   3. Acylation with acid halides or anhydrides.




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                                  Bioorganic chemistry for Medicine students
                                                           O
                                                   R'
                                     R       O                      R        O
                                                           Hal

                                  H2N          OH                           HN               OH
                                                                                        R'
                                                                             O
   4. Reaction with nitrous acid to form hydroxyl acid.
                                           R        O       HNO 2       R           O

                                      H2N           OH              HO              OH
       Action of heat
       The behavior of amino acids on heating is similar to that of hydroxyl acids.
   1. Alpha-amino acids lose two molecules of water between two molecules of the acid to form
       cyclic amides known as diketopiperazines.
                                          R     O
                                                                                O
                                                                    R
                                      H2N       OH                                  NH
                                      HO        NH 2                    HN
                                                                                            R
                                          O     R                               O
   2. Beta-amino acids split out a molecule of ammonia and yield α,β-unsaturated acids.

                                  R                 O                   R                       O

                                       NH 2    OH                                       OH

   3. Gamma-amino and delta-amino acids lose a molecule of water between NH2 and COOh
       groups of the same molecule to give cyclic amides called lactams.
                                                        O
                                  H2N
                                                                                                O
                                                        OH                          N
                                      R                                 R           H
                                                    Proteins
       Proteins are a class of most important compounds that are found in living organism. They
are the main organic constituents of the body such as muscle, skin, hair and nails. They carry out all
vital processes in the human system.
       Proteins are built up of a large number of α-amino acid molecules interlocked by elimination
of water between NH2 group of one acid molecule and COOH group on the other.
                                                                                        O           R'
                        R     O           R'        O
                                                                            R                                 O
                                                                                             N
                    H2N       OH       H2N          OH                                       H
                                                                                 NH 2                    OH

       In this way the long chains are built up from 200 to 60000 amino-acid units, and relative
molecular masses from 17500 to 6000000.
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                                  Bioorganic chemistry for Medicine students
Structure of proteins – peptides
       Amino acids are bifunctional molecules with NH2 group at one end and COOH group at the
other. Therefore, COOH of one molecule and NH2 of another molecule interact by elimination of
water to form an amide-like linkage.
                                                                         O         R'
                       R      O         R'       O
                                                                  R                          O
                                                                               N
                    H2N       OH      H2N        OH                            H
                                                                      NH 2              OH

       The product is peptide and the grouping –CO-NH- is called a peptide linkage. Peptides are
further designate as di, tri, and tetrapeptides according as they contain two, three, four amino acid
molecule joined together in this fashion.




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                                                  Lecture 14
                                                Carbohydrates
       The carbohydrates are an important class of naturally occurring organic compounds. These
include glucose (grape sugar), fructose (honey), sucrose (cane sugar), starch (potatoes), and
cellulose (wood). They are all composed of C, H and O.
       The carbohydrates are polyfunctional compounds. They contain the following functional
groups:
   1. Alcoholic hydroxyl groups, -OH
   2. Aldehyde group, -CHO
   3. Ketone group, -C=O
The carbohydrates are divided into three major classes depending on the number of single sugar
units present in their molecule:
   1. Monosaccharides (simple sugar). These are single unit carbohydrates that cannot be broken
          into simpler carbohydrates upon hydrolysis.
   2. Oligosaccharides. They are made of 2 to 10 units of monosaccharides or simple sugar. The
          oligosaccharides containing two monosaccharide units are called disaccharides.
   3. Polysaccharides. They contain more than 10 monosaccharide units in the molecule. Thus
          one molecule of starch or cellulose upon hydrolysis yields a very large number of glucose
          units.
       The monosaccharides are classified on the basis of two factors:
   1. By the carbonyl function. Those containing the aldehyde function, -CHO, are called
          Aldoses. Others containing the keto group. –CO-, are called Ketoses.
   2. By the number of carbon atoms (3 to 8) in the molecule. The monosaccharides containing
          3, 4, 5, 6, etc., carbon atoms are designated as trioses, tetroses, pentoses, hexoses, and so
          on.
D and L designation
       Glyceraldehyde contains a central asymmetric carbon atom (all four substituents are
different). Therefore, it exists in two enantiomers (or mirror image isomers) represented by the
Fischer projection formulas (1) and (2).
                                     CHO                           CHO
                                H        OH                  HO        H
                                     CH 2OH                        CH 2OH

                              D (+ )-glyceraldehyde         L (- )-glyceraldehyde
                                     (1)                            (2)

       In 1906 Rosanoff decided arbitrarily tat the enantiomer (1) with OH to the right may be
designated as D-glycerakdehyde and the enantiomer with Oh to the left as L-glyceraldehyde.
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                                      Bioorganic chemistry for Medicine students
        The sugar are divides into two families, the D-family and the L-family, taking the
configuration of glyceraldehydes as starndard. The sugar having the same configuration as of D-
glyceraldehyde at the asymmetric carbon most distant from the carbonyl group are designated as D-
sugar. Those with opposite configuration (that of L-glyceraldehyde) are called L-sugars. Thus
natural dlucose is D-glucose and fructose is D-fructose.
                                              CHO                                 CHO
                                          H       OH                      HO           H
                                          H       OH                      HO           H
                                      HO          H                           H        OH
                                          H       OH                      HO           H
                                              CH 2OH                              CH 2OH

                                      D-glucose                               L-glucose



                                                      Monosaccharides
        They are the simplest one-unit sugar.
        CHO                  CHO                       CHO                    CHO                          CH 2OH        CHO
   HO         H          H        OH              H       OH          HO           H                          O      H     OH
   HO         H         HO        H               H       OH              H        OH          HO             H     HO     H
    H         OH        HO        H               H       OH              H        OH              H          OH     H     OH
    H         OH         H        OH              H       OH              H        OH              H          OH     H     OH
        CH 2OH               CH 2OH                    CH 2OH                 CH 2OH                       CH 2OH      CH 2OH
   D-mannose            D-galactose               D-allose                D-altrose                    D-fructose    D-glucose

        We know that a carbonyl compound (aldehyde or ketone) reacts with an alcohol to form a
hemiacetal.
                                              O                                   H
                                      R           + HOR'                      R         OH
                                              H                                   OR'

        In carbohydrates we have an aldehyde (ketone) group which combines with an alcoholic OH
of the same molecule to form an internal hemiacetal.
        For example, glucose forms a stable cyclic hemiacetal between the CHO group and the OH
group on the fifth carbon atom. In this process the first carbon atom becomes asymmetric, giving
two isomers (1 and 2) which differ in the configuration of the asymmetric carbon atom.
                    H        O                               H       OH                 HO          H
                        C                                        C                             C
                    H        OH                            H         OH                    H           OH
                    H        OH                            H         OH O                  H           OH O
                   HO        H                           HO          H                 HO              H
                    H        OH                            H                               H
                        CH 2OH                                   CH 2OH                        CH 2OH
                    D-glucose                            1 D-glucoseD-glucose
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                                  Bioorganic chemistry for Medicine students
       Theses are called anomers and the new asymmetric carbon is referred to as anomeric
carbon. The anomer 1 with OH to the right is designated as the α-D-glucose and the other with OH
to the left β-D-glucose.
       Usually for cyclic forms of sugar the following forms are used:
                                                       CHO
                                                  H       OH          HO OH
                HO OH
                                                  H       OH                          HO
                             HO
               H                                HO        H          H
                   H                 H                                    H                  OH
                         H                                                       H     OH
                              OH                  H       OH
                       OH       OH                                             OH        H
                                                       CH 2OH
                   -D-glucose                                                -D-glucose

Chemical properties
       We have seen that hexoses are an equilibrium mixture of a straight chain form and two
hemiacetal form. Even though it is mainly the hemiacetal form, hexoses give the characteristic
reactions of simple aldehydes.
       Reaction in the open-chain form
       Oxidation
           1. With weak oxidizing agents. On treatment with a weak oxidizing agent such as
               bromine water, CHO group of hexoses is oxidized to COOH group.
                                              CHO                             COOH
                                          H       OH                  H          OH
                                                         Br2/H2O
                                          H       OH                  H          OH
                                         HO       H                 HO           H
                                          H       OH                  H          OH
                                              CH 2OH                          CH 2OH

           For the same reason, hexoses reduces Tollen‟s reagent (Ag+) and Ferling‟s solution
           (Cu2+) to give metallic silver and cuprous oxide, respectively.
           2. With strong oxidizing agents. A strong oxidizing agent like nitric acid oxideses both
               the CHO and CH2OH groups of hexoses.
                                              CHO                             COOH
                                          H       OH                  H          OH
                                                          HNO 3
                                          H       OH                  H          OH
                                         HO       H                 HO           H
                                          H       OH                  H          OH
                                              CH 2OH                          COOH

       Reduction
       Hexoses on reduction with sodium borohydride (NaBH4) or catalytic (H2/Pt) reduction give
the corresponding alcohols.


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                                   Bioorganic chemistry for Medicine students
                                        CHO                          CH 2OH
                                    H         OH                        H            OH
                                                      NaBH 4
                                    H         OH                        H            OH
                                   HO         H                     HO               H
                                    H         OH                        H            OH
                                         CH 2OH                              CH 2OH

         Addition of HCN
         Like other aldehydes, hydrogen cyanide reacts by addition at the aldehydic carbonyl group.
Since this creates a new asymmetric carbon atom. Two isomeric cyanohydrins differing only in
configuration at the aldehydic carbon are obtained.
                                                               CN                         CN
                              CHO                       H           OH           HO            H
                          H        OH                   H           OH               H         OH
                                             HCN
                          H        OH                   H           OH       +       H         OH
                        HO         H                   HO           H            HO            H
                          H        OH                   H           OH               H         OH
                              CH 2OH                           CH 2OH                     CH 2OH

         Reaction with hydroxylamine
         Hexoses condense with hydroxyl amine to form oximes.
                                        CHO                                 CH=N-OH
                                   H         OH                     H            OH
                                                    NH 2OH
                                   H         OH                     H            OH
                               HO            H                  HO               H
                                   H         OH                     H            OH
                                        CH 2OH                              CH 2OH

         Reaction with phenylhydrazine
         When warmed with excess of phenylhydrazine, glucose first forms phenylhydrazone by
condensation with the CHO group. The reaction does not stop at this stage. The adjacent CHOH
group is then oxidized by a second molecule of phenylhydrazine which itself is reduced to give
aniline and ammonia. The resulting carbonyl group reacts with a third molecule of the reagent to
yield the final product glucosazone.
          CHO                       CH=N-NHPh                               CH=N-NHPh                     CH=N-NHPh
     H       OH                H         OH                                      O                           N-NHPh
                                                                                          NH 2NHPh
     H       OH NH 2NHPh       H         OH        NH 2NHPh         H            OH                   H      OH
   HO        H                HO         H                      HO               H                   HO      H
     H       OH                H         OH                         H            OH                   H      OH
          CH 2OH                    CH 2OH                                  CH 2OH                        CH 2OH

         Reaction in the cyclic form
         Acetylation

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       Hexoses react with acetic anhydride or acetyl chloride to form penta-acetyl hexose.
                               OH                                               OAc
                       HO                                           AcO
                                        HO              Ac2O                             HO
                       H                                                H
                           H                       H                        H             H
                                  H       OH                                      H OAc
                                OH          OH                                  OAc    OAc
                                               O
                               Ac= H3C


       Reaction with alcohols
       When a hemiacetal form is treated with an alcohol in the presence of a trace of acid, an
acetal is formed.
                           OH OH
                                                                        HO OH
                                        H O                     +                        HO
                                                       R'OH/H
                       H                                                H
                           H                       H                        H                         H
                                 H       OH                                       H           OH
                               OH          OH                                   OH              OR'



                                                   Disaccharides
       Disaccharides are carbohydrates that produce two monosaccharides on hydrolysis.
       In a disaccharide, the two monosaccharides are joined together by acetal or glycoside
formation. The hemiacetal OH of one monosaccharide and an OH of the second monosaccharides,
dehydrate to establish the bond ( called glycosidic bond) between the two monosaccharides.
       Sucrose (cane sugar)
       Sucrose is ordinary table sugar. It is obtained from cane sugar. Sucrose is composed of α-D-
glucose unit and β-D-fructose unit. These unit are joined by α,β-glycosidic linkage between C-1 of
glucose and C-2 the fructose unit.

                       HO OH                                        HO OH
                                        HO                                           HO
                       H                                            H
                           H                       H                    H                         H
                                 H       OH            H2O                     H         OH
                               OH          OH                                OH
                                                                        HO
                        HO                                                                    O
                                          OH                                          O
                                     O                                              H HO
                                   H HO
                                                                                H             CH 2OH
                               H              CH 2OH                                OH    H
                                   OH     H
       Notice that in the above structure of sucrose, hemiacetal structure is missing. That is why
sucrose: 1) does not form an osazone with phynylhydrazine; 2) does not reduce Tollen‟s resgent or
Fehling‟s solution (sucrose is a non-reducing sugar).
       Maltose
       It is obtained from starch. It is composed f two α-D-glucose units joined by an α-glycosidic
linkage between C-1 of one unit and C-4 of the other unit.
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                                            Bioorganic chemistry for Medicine students
     HO OH                      HO OH                                 HO OH                        HO OH
                    HO                          HO                                    HO
    H                                                                                                              HO
                                H                                     H
        H                   H       H                     H -H2O                                   H
              H      OH                   H                               H                    H       H                   H
                                                   OH                           H      OH                  H        OH
            OH         OH               OH           OH                       OH                   O                  OH

        Notice that C-1 of the second glucose unit in the maltose structure is a hemiacetal carbon.
Consequently, it is in equilibrium with the open-chain aldehyde form. Thus maltose can exist in α
and β form. Since it has a potential aldehyde group, therefore forms osazone, and reduces Ferling‟s
solution (Maltose is a reducing sugar).
        Lactose (milk sugar)
        It is found in the milk of all animals. Cow‟s milk contains 4-5% and human milk 6-7%
lactose. Lactose is composed of β-D-galactose unit and α-D-glucose unit joined by β-D-glycosidic
linkage between C-1 of the galactose and C-4 of the glucose unit. Since it has a potential aldehyde
group, therefore forms osazone, and reduces Ferling‟s solution (Lactose is a reducing sugar).


    HO OH                                                              HO OH
                                    HO OH                                                              HO OH
                    HO                                                                HO
                             +                     HO                                                              HO
   H                                                                   H
   HO                      OH H                                        HO                      OH
                H    OH                 H                    H                    H      OH            H                   H
                                               H      OH                                                       H    OH
            H          H                                                      H            H
                                             OH         OH                                                            OH




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