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Ethers_ Sulfides_ Epoxides

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					                     Carbenes, :CH2
Preparation of simple carbenes
  1.



                                 carbene


  2.


  Mechanism of the a elimination.
         Reactions of Carbenes, :CH2 (not for
                      synthesis)



Addition to double
bond.
                              liquid

Insertion into C-H bond




Formation of ylide (later)
Simmons Smith Reaction (for synthesis,
addition to alkenes to yield cyclopropanes)


          CH2I2   + Zn(Cu)         ICH2ZnI
                                 Carbenoid, properties
                                 similar to carbenes.
Electronic Structure




            Electrons paired, singlet
        Triplet and Singlet Methylene
              Dominant form
                                     Gas phase
              in solution

CH2N2

                                                                  Rotation can
            singlet carbene         triplet carbene             occur around this
                                                                      bond.


                     pi electrons




                                             CH2
                                                                     +

            stereospecific
            addition
                                     diradical
                                                      non-stereospecific
Aldehydes and Ketones

      Chapter 16
                          Structure
Aldehydes                            Ketone

        O           Carbonyl           O
                    group

    R       H                    R             R




                    sp2
                               2-pentanone
                                           O
    pentanal
                O
                        Examples of Naming
                                                 OH
                   O                                                               O



                                                      O
         pentan-2-one                                               O

                                                                           3-oxopentanal

        O         O
                                 2-(1-hydroxyethyl)pentanal
                                                                                            CHO


                                                              CH3
                                                      H             CHO


                                                      H             CO2H
                                                              CH3
                                                                                       benzaldehyde
                                            2,3-dimethyl-4-oxobutanoic acid
(E)-3-(but-1-enyl)hexane-2,4-dione
         Resonance
           O               O




                  
                       O
result
Extension of resonance




              O          O
                     Boiling points
For compounds of comparable molecular weight…


Alkanes, ethers < aldehydes, ketones < alcohols < carboxylic acids

                  Dipole-dipole           Hydrogen Bonding
Dispersion
Forces


               Water Solubility
Ketones and Aldehydes, like ethers, can function as hydrogen bond
acceptors and smaller compounds have significant water solubility.
   Recall Preparation from Alcohols
                             OH                            OH

Can also be
done using                            Na2Cr2O7

KMnO4 in base                                                     Be sure you
with heat or       HO
                                       acid, 35 deg.
                                                       O
                                                                  can balance
bleach in acid                                                    this kind of
solution                                                          reaction.
                              CH2OH                        CO2H
(HOCl).
Use PCC to limit oxidation of primary alcohol to the aldehyde.
Secondary are oxidized to ketone.
Primary alcohol
             PCC
    RCH2OH                RCH=O


 Secondary
                 PCC
    R2CHOH                 R2C=O
                Preparations, con’d
• Reaction of acid chloride and Gilman
           O




     R           OH

                       SOCl2

                                    O
         Na2Cr2O7
                                                         O
    RCH2OH
                               R          Cl


                                                     R       R'



                               R' 2CuLi


               1. Li
                                   But where do we
                                   get these??
         R'X    2. CuX
 Note that we have two possible disconnects available



                      HOCH2R

                                            R'OH


                         O

                                    + R'X

     O           HO             R



R'       R
                        O

                                    + RX

                 R'          OH


                                            ROH
                      HOCH2R'
        Example: Prepare 2-butanone from ethyl alcohol

Requirement to start with ethanol suggests a disconnect into two carbon fragments.



                                               CH3CH2OH

                     O
                                                             Done!
                                         CH3CO2H + CH3CH2X


                             via Gilman and
                             acid chloride
    Aldehydes from carboxylic acids

                                      Reduction



    O    SOCl2       O   LiAlH(OC(CH3)3)3          O




R       OH       R         Cl               R           H




        And from alcohols, as before:
                     PCC                        Oxidation

        RCH2OH                      RCHO
             A Common Sequence
             PCC
   RCH2OH                RCHO               OH




            PX3         Mg              R          R'
   R'OH            RX           R'MgX

                                                Na2Cr2O7



                                            O



Observe these parts at this moment.     R         R'
                                      Reactions
  Addition of a nucleophile: Nucleophilic Addition

   Good nucleophile, usually basic
                                  O
                                             O                     O


                                                       +                    Attack of
                        Nu:   -
                                             Nu                    Nu       nucleophile
                                            tetrahedral intermediate
                                                                            occurs on both
                                                                            sides of carbonyl
                                                                            group.

                                              OH
                                                                            Produces both
                                                                       OH
                                                                            configurations.
                                                        +

                                              Nu                       Nu


Overall: H – Nu was added to carbonyl group double bond.
Notice that the CO bond order was reduced from 2 to 1. The addition reduced the bond
order. We will use this idea later.
  Reaction can also be done in acid environment.
  Nucleophiles not expected to be as strong (why?) but the oxygen may
  become protonated making the carbonyl a better electrophile
  (why?).

      O                  OH
          acid                                   OH              OH

                                                          +


                   Nu:                           Nu              Nu




                                    Very electronegative,
                                  protonated oxygen. Pulls
                                  the pi electrons into itself
                                           strongly.


Problem: If there is too much acid present the nucleophile may become
protonated, deactivating it
        Addition of Grignard (Trumpets Please)

  Recall the formation of a Grignard and its addition to an oxirane
                                         O


                  Mg                                        OMgX


        R-X                 R-Mg-X
                ether
                                                  R
                                  O
Carbonyls may be added to
                                                  OMgX
in same way…                                                         OMgX


         Mg                                             +
R-X                R-Mg-X
        ether                                     R                  R

        If a new chiral center is                      mild acid
        created both configurations
        will be produced.                         OH                 OH




                                                  R                  R
        Common Reactions of Grignards
     R2R'COH                                     ROHRXRH(D)                   OH

     a tertiary alcohol                  R-H                                                Both of these
                                                                                            reactions extend
Examine reaction                           acid,            O     R                         carbon chain &
                             R'CO2Et       weak acid
with ester further.          an ester                                     primary alcohol   keep -OH
                                                                      O
                                                                                            functionality at
ROH + R’CH2OHRX + R’CO2HR2C(OH)R’                                                         end of chain.
                      O
                                        R-Mg-X                                              Can extend
                                                              H            H
                                                                                            further.
                                                                                  RCH2OH
               R'           R''                  O
                                                                  CO2             primary alcohol


                                           R'          H
  RR'R''C-OH
  tertiary alcohol

ROH + R’R”CHOH                          RCHR'                                                  RCO2H
                                                  secondary alcohol
                                                                                        carboxylic acid
RX + R’R”CO              RR’C (OH)R”     OH

                                                                                 ROHRXRCO2H

               ROH + R’CH2OHRX + R’CHORCH(OH)R’
       Grignard Reacting with an Ester.
       Look for two kinds of reactions.
                                                                       O                              OMgX
                     O                              O
                                  R-Mg-X                                       R-Mg-X

                                           R'            OEt                            R'                     R
                                                                R'         R
              R'            OEt                 R                                                 R
                                                        Substitution
Any alcohol
will do              EtOH
                                    But where does an ester
here.                               come from?                                                            OH
              R'COCl       Acid
                           chloride
                                                                                             R'                R
                                                                                                      R
                   SOCl2
                             Perhaps this carboxylic acid
                                                                                        Addition
                             comes from the oxidation of a
              R'CO2H
                             primary alcohol or reaction of
                             a Grignard with CO2.
Synthetic Planning… Use of epoxides and
 carbonyls offer different disconnect sites.                              Pattern

                                       O
                                               1. RMgX       HO           HO-C-C-R
                                               2. H2O, HCl
  epoxide
                                                                      R


                                                                             Nucleophile
                                                 New bond.
                                                 Disconnect site.


                         O                     OH
                              R-Mg-X                         New bond.       Pattern
 carbonyl                                                    Disconnect
                                           R                     site        HO-C-R




                                                                  Want this to be
                                                                  the nucleophile
                                                                    (Grignard).
 Patterns to recognize: carbonyl vs
               oxirane
We can create the following fragments of
 target molecules by using an
 organometallic (carbon nucleophile)
     reaction with a carbonyl


               O          RMgX   dil. acid   OH


                                                      The difference is the
                                                      extra CH2 when using
                                             R
                                                      an oxirane.
     reaction with a oxirane



           O             RMgX    dil. acid   OH




                                                  R
           Synthetic Planning…

                 Three different disconnects possible



                                    OH
Give synthetic                                                O

routes to                                                                   + R3-Mg-X
                                    C
                                                     R1                R2
                          R1             R3
                               R2


                                                          O


                                                                       + R2-Mg-X
                      O
                                                R1                R3

                                + R1-Mg-X
                 R2        R3




                           If none of the Rs are H then these three synthetic
                           routes may be available.
                  Example: Synthesize from ethanol
                                                 CH3CH2OH

                                      CH3CH2X
            O


                                          OH




                                                                       Done
                      OH
                                                MgX   CH3CO2Et
                                  2



                  O
                                                  CH3CO2H   CH3CH2OH
    CH3CH2MgX                  CH3CH2OH



                             Preliminary Analysis
•Hmmm, even number of carbons, at least that is good; ethanol is a two
carbon molecule.
•Now the problem is to divide it up into smaller fragments.
•Ether linkage is easily constructed. Williamson.
•Two butyl groups attached to the central 2 carbon fragment. Grignard + ester.
                               Bisulfite Addition




             O
                                         O                           OH




                                         S                           S
             S                      HO       O                   O        O
        HO       O
                                         O                           O
             O



                                                          Addition product.



Practical importance: liquid carbonyl compounds can be difficult to purify. The
bisulfite addition products will be crystalline and may be recrystallized.
          Addition of Organolithium
          Compounds to Carbonyls
Generally the reactions are the same as for Grignards but the lithium
compounds are more reactive (and more difficult to handle).
                                               O

                                   O                             OH

         Br               Li


                Li
                                                    mild acid




 bromocyclohexane
                                 Decreased reactivity of
                                 electrophile due to steric
                                 hindrance to attack. So we
                                 used the alkyl lithium instead of
                                 a Grignard.
      Nucleophiles derived from terminal alkynes



                                  Can do all the reactions of an
For example, once                 alkyne and an alcohol. But
formed, the new                   remember that we have two
alkynyl alcohol can be            acidic groups: the more acidic
hydrated in two ways,             OH and the less acidic terminal
Markovnikov and anti              alkyne. We discussed this
Markovnikov.                      problem earlier.
                                               Note that the
                                               regioselectivity
                                               used here is only
 Carefully observe the
                                               effective if this
 structure of the
                                               alkyne is terminal.
 products, the
                                               Otherwise get a
 relationship of the OH
                                               mixture.
 and the carbonyl.
    Addition of hydrogen cyanide

                                      basic




Think of what the mechanism should be….
                                                          pH issue.
                                                          Slightly basic
                                                          media so that
                                                          HCN has
                                                          partially
                                                          ionized to
Followed by protonation of the alkoxide ion (perhaps by   cyanide ion,
unionized HCN).                                           the actual
                                                          nucleophile.
         Follow-up reactions on the
              cyanohydrins…
                                                              H2O
                                                      R



                                                                          N
                                                    RHC

                                acid catalysis
                                dehydration
                                                      We saw this hydrogenation before.
                           OH
    O           dil acid
         NaCN                                                                 OH
                                                       H2
                                                                                     NH2
                    R                 N
R       CH2R
                           CH2R                    catalyst           R
                                                                              CH2R
                                                 Hydrolysis. Acid, heat
                                                 or
                                                 base, heat OH



                                                                    CO2H
                                                       R
                                                               CH2R
         Let’s see what we can do with the mechanism of the
        hydrolysis of the nitrile group to a carboxylic acid.
  Overall
                             aq. acid, heat                              + NH3
                                                           R
            R
                                                                CO2H

                       N

        The action is at the nitrile group, CN --> CO2H.
        But how does a nitrile group behave? What could be happening?
        We are breaking the CN bond; bond order goes from 3 to 0. Probably stepwise.
        Chemically speaking: the nitrogen of the nitrile is basic (lone pair) and can
        be protonated. This makes it a better electrophile (cf. carbonyl). Multiple
        bond can undergo addition (cf. carbonyl) reducing bond order.
Goal: Break the C to N bonding and create C-O bonds.
Considerations: neither the electrophile (RCN) nor the nucleophile (water) is very
reactive. Since we are in acid protonate the CN group to make it a better electrophile.
Then attack it with the water nucleophile to add water. This results in reduction of C-N
bond order and creation of C to O bonds .
Again, we are in acid environment. Let’s protonate something….
Protonate the multiple bonded N atom to make better electrophile and attack with
the nucleophile, water.
                                                      Note the bonding pattern here. We have seen it before.
                  R            acid
                                       R

                           N
                                                  HO             NH
                                                                              similar to
                                            NH                                             HO         CH2
                                                                      which tauermerizes in acid or base, keto-enol




                                                 HO             CH2
                                                                                       O




              R                         R                   R                                   R

                                                                            + H+                            + H+
                      NH
                                            NH                         NH                               NH2
                                      H2O                HO                                     O
        HOH


  What have done so far? Reduced the CN bond order from 3 to 2 and added one
  O to the C. Moving in the right direction!
  Want to reduce the CN bond order to zero and introduce more O on the C. Keep
  going! To induce the water to attack again (adds another O) need to increase
  the reactivity of the electrophile. Protonate again!! On the O.
          R                              HOH
                    acid
                                   R

                   NH2                                                          OH2
         O                                                                R
                                           NH2
                                 O

                                 H                                                    NH2
Initial equilibrium with acid                                            HO



      Now want to get rid of the NH2. We have all the O’s we need.
      We know what we have to do. Have to get the N protonated to
      make it a good leaving group.
                    OH2
                                                          H
              R
                                                                                + NH3
                                 reposition the H+            O
                           NH2
              HO                                     R
                                                                                  O
                                                                          R
                                                                  NH3
                                                     HO

                                                                          HO




                                                                        Done.
                  Wittig Reaction
                                           O




       H      I             Bu-Li      R       R
                  PPh3

                           or NaH
                                                   R   R
              Substitution Elimination


Example, synthesize            CHCH3




                      or combine them the other way…
              Wittig Reaction Mechanism
                           H
                                                     H                     Acidic
                                   I
                                                                          hydrogen
                                             Ph3P
       Ph3P:      +
Nucleophilic substitution                                                      Nucleophilic
                          H
                                       strong base, BuLi
                                                                                  center
                Ph3P
                                                             Ph3P       Phosphonium ylide
                                                                    R                     R
                                                         O
                               O                                                O
                                                                    R                     R

                  +                                                           Ph3P
                                                    Ph3P
Ph3P                   R               R

                                                                                oxaphosphetane
                                                    betaine
                   R
                                                      R         R
         O
                   R

       Ph3P                                 Ph3PO


         oxaphosphetane
Friedel Crafts Acylation


                            R     O
                   O




           R           Cl




           AlCl3




                            And then all the
                            reactions of ketones…
Formation of Hydrates, carbonyls
          and water.




Carbonyl side of equilibrium is usually favored.
      Hemiacetals and Acetals, carbonyls and alcohols

Addition
reaction.
                                              (Unstable in
                                              Acid; Unstable
                                              in base)




                                              (Unstable in
                                              Acid; Stable in
                                              base)


               Substitution reaction
   Formation of Hemiacetals, catalyzed by either
       acid or base. Let’s do it in Base first.
But first let’s take stock.
We have an addition reaction.
 Just mixing a carbonyl and an
 alcohol do not cause a
Use Base to
 reaction.
set-up good
necleophile. must be made a
 One of them
 better reactant.

                   Poor into a
Carbonyl can be madenucleophile     Good nucleophile
better electrophile by
protonating in acid.
Alcohol can become a better
nucleophile in base by                         An addition of the
ionization.                                    alcohol to the carbonyl
                                               has taken place. Same
                                               mechanism as
                                               discussed earlier.
                                  hemiacetal
    Alternatively, hemiacetal formation
                   in Acid
Protonation of
carbonyl (making the
oxygen more
electronegative)


Attack of the (poor)
nucleophile on (good)
electrophile.



 Deprotonation



Overall, we have added
the alcohol to the
carbonyl.
    Hemiacetal to Acetal, Acid Only



 Protonate the hemiacetal,
 setting up leaving group.


Departure of leaving
group.


Attack of
nucleophile

                               Substitution
Deprotonation
                               reaction, cf
                               S 1.
                         Equilibria
Generally, the hemiacetals and acetals are only a minor component of an
equilibrium mixture. In order to favor formation of acetals the carbonyl
compound and alcohol is reacted with acid in the absence of water. Dry
HCl) The acetals or hemiacetals maybe converted back to the carbonyl
compound by treatment with water and acid.
An exception is when a cyclic hemiacetal can be formed (5 or 6 membered
rings).
              Hemiacetal of D-Glucose
The alcohol
                  The carbonyl


                                                                     Try following
                                                                     the
                                                                     stereochemistry
                                                                     here for
                                                                     yourself

   The hemiacetal can form with two different configurations at the carbon of the
   carbonyl group. The carbon is called the anomeric carbon and the two
   configurations are called the two anomers. The two anomers are
   interconverted via the open chain form.
Stabilities of the Anomers…
Here note the alternating up-down relationships.


                                            More stable b form, with the
                                            OH of the anomeric carbon is
                                            equatorial


                                            Less stable a form.




      Here see the cis relationship of these two OH groups, one
      must be axial.
             Cannizaro Reaction
                             conc. KOH
Overall:
                 2 RCHO                       RCO2- + RCH2OH
                             heat


   Restriction: no a hydrogens in the aldehydes.
                                    CHO             CHO
                         O                H




                   H3C




                   a hydrogens                 No a hydrogens

Why the restriction? The a hydrogens are acidic leading to ionization.
                             Mechanism
What can happen? Reactants are the aldehyde and concentrated hydroxide.
Hydroxide ion can act both as
    Base, but remember we have no acidic hydrogens (no a hydrogens).
    Nucleophile, attacking carbonyl group.



                                                                                   O
              O
                                     O                        O
                                                                                                R
                                                                                        +   H
                                                  R                +           R
          R         H
                                 R        H               R                         O
                                                                       R                    H       OH
              -                      OH                       OH
           HO :                                                    H
                                              H       O
                  Attack of                                        H       O

                  nucleophilic       Re-establish C=O and                          Acid-base
                  HO-                eject H- which is
                                     immediately received
                                     by second RCHO
Experimental Evidence
         KOH, H2O
2 RCDO                   RD2OH + RCO2-




         These are the hydrogens introduced by the
         reaction. They originate in the aldeyde and do
         not come from the aqueous hydroxide solution.
Kinetic vs Thermodynamic Contol of a
               Reaction
  Examine Addition of HBr to 1,3 butadiene

                                                                             H
                                                  H
                    HBr
                                                      +



                                                          Br
                                             Br




                                    1,2 product                1,4 product
                           Mechanism of reaction.




                     Allylic resonance
                                                  H
                               H

        H-Br




                     Br            Br

                                                      H
                          H




                                   Br
                     Br

                 1,2 product            1,4 product




But which is the dominant product?
Nature of the product mixture depends on the temperature.


                                                                                 H
                                                      H
                        HBr
                                                          +



                                                              Br
                                                Br




                                        1,2 product                1,4 product


          Product mixture at -80 deg       80%                        20%
          Product mixture at + 40 deg      20%                        80%



Goal of discussion: how can temperature control the product mixture?
 When two or more products may be formed in a reaction A  X or A  B

Thermodynamic Control: Most stable product dominates


Kinetic Control: Product formed fastest dominates



 Thermodynamic control assumes the establishing of equilibrium conditions
 and the most stable product dominates.



 Kinetic Control assumes that equilibrium is not established. Once product is
 made it no longer changes.



 Equilibrium is more rapidly established at high temperature. Thermodynamic
 control should prevail at high temperature where equilibrium is established.
 Kinetic Control may prevail at low temperature where reverse reactions are
 very slow.
Nature of the product mixture depends on the temperature.


                                                                                  H
                                                       H
                        HBr
                                                           +



                                                               Br
                                                  Br




                                        1,2 product                 1,4 product


          Product mixture at -80 deg       80%                         20%
          Product mixture at + 40 deg      20%                         80%



                                                                            More stable
Thermodynamic Control                                                       product
                                Kinetic Control

                                              Product formed most
                                              quickly, lowest Ea
Formation of the allylic carbocation.


Can react to yield 1,2 product or 1,4 product.
Most of the carbocation reacts to give the 1,2 product because of the
smaller Ea leading to the 1,2 product. This is true at all temperatures.
At low temperatures the reverse reactions do not occur and the product
mixture is determined by the rates of forward reactions. No
equilibrium.
Most of the carbocation reacts to give the 1,2 product because of the
smaller Ea leading to the 1,2 product. This is true at all temperatures.
At higher temperatures the reverse reactions occur leading from the
1,2 or 1,4 product to the carbocation. Note that the 1,2 product is more
easily converted back to the carbocation than is the 1,4. Now the 1,4
product is dominant.
      Diels Alder Reaction/Symmetry Controlled Reactions

  Quick Review of formation of chemical bond.




            Electro       Electron
            n donor       acceptor




Note the overlap of the hybrid (donor) and the s orbital which allows bond formation.


                      For this arrangement there is no overlap. No donation of
                      electrons; no bond formation.

				
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