Aromaticity
4/19/06
Cyclobutadiene & Cyclooctatetraene
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Cyclobutadiene
Aromatic?
Cyclooctatetraene
Observations:
•Cyclobutadiene and cyclooctatetraene are difficult to prepare.
•Intraring bond distances in stable cyclobutadiene derivatives are not equal.
•Resonance energy for cyclooctatetraene is very low.
•Cyclooctatetraene is not a planar molecule.
Conclusion:
Cyclic conjugation is a necessary but not sufficient requirement for aromatic character!
What more is needed?
Hückel’s Rule
Hückel’s Rule - Annulenes
The year 1931! Hückel’s Discovery - An early success using molecular orbits to
understand chemistry.
Analysis of MOs for Monocyclic Conjugated Polyenes with Regular Polygons
having Planar Geometries
•Said hydrocarbons are characterized by a set of p-molecular orbitals in
which:
•One (1) orbital is of lowest energy (p-bonding);
•Another is of highest energy (p*-antibonding);
•The rest are distributed in pairs between them (Some p-bonding, an
equal number as p*-antibonding, and in some cases some nonbonding).
Constructing the p-Orbital MO Diagrams
1. Draw the polygon representing the ring of interest with one apex at the bottom of the drawing.
2. Place an orbital at each corner of the polygon.
3. Fill the orbitals with electrons in the usual manner.
1. Pair electrons in lower energy orbitals before filling higher energy orbitals.
2. Closed shells are favorable (aromatic, 4n+2) unshared electrons in orbitals are not (antiaromatic,
4n).
p*4 p*6 p*8
p*6 p*7
p*4 p*5
p2n p3n p4n p5n
p2 p3 p2 p3
p1 p1 p1
Cyclobutadiene Benzene Cyclooctatetraene
Interpreting the MO Figure p *
8
p*6
p*5
p2n p3n p4n p5n
p3
p2
p1 p1
p1
Cyclobutadiene Benzene Cyclooctatetraene
Color coding of orbitals in the energy diagram: green = bonding (energy released), blue = nonbonding (no
change in energy), & magenta = anti-bonding (absorb energy).
•Placing electrons in bonding orbitals adds stability to the compound.
•Placing them in the nonbonding orbitals has no effect on compound’s stability.
•Placing electrons in anti-bonding orbitals decreases the stability.
•When all orbitals below the “blue” line are filled with electrons and none are in or above the blue line the
system has a “closed shell” electron configuration.
Hückel’s 4n+2 Rule
Monocyclic planar, fully conjugated polyenes are called
annulenes.
Among annulenes, only those possessing 4n+2 p electrons,
where n is an integer, will have special aromatic stability.
– Planarity and complete conjugation are important criteria.
– The 4n+2 rule may be fulfilled for neutral or ionic moieties.
Cycloheptatriene & the Cycloheptatrienyl Cation
H H H
+
Cycloheptatriene Cycloheptatrienyl Cation
Cycloheptatriene (the tropylium cation) has a conjugated, but not a fully conjugated
structure.
The conjugation is interrupted by the presence of the sp3-hybridized carbon atom.
Ionization of cycloheptatriene by removal of a hydride ion (H-) converts this carbon to
an sp2 hybrid and allows the conjugation of the triene moiety to “close ends” via the
empty p-orbital making a fully conjugated system.
The Cycloheptatrienyl Cation p-MO Diagram
There are 7 p-orbitals which give rise to seven p MOs.
•There are 3 bonding orbitals
•The remaining four orbitals are antibonding
•There are six available electrons that fill the bonding orbitals making a
closed shell
•Note 4n + 2 = 6. The cation is planar and aromatic!
Additional Aromatic Ions
H H H H
- +
-H+ -H-
Cyclononatetraene can form either a anion (removal of a proton) or an cation
(removal of a hydride ion).
Which if any is a viable candidate for aromatic stabilization?
Answer:
•The cation has 8 p electrons and therefore is not viable.
•The anion has 10 p electrons and therefore is viable.
•Propose a MO diagram for the anion that is consistent with aromatic stabilization.
Answer
A Couple More Examples
H H H
2-
+
-
H
H H
Cyclopropenyl Cyclopentadienyl Cyclooctatetraene
Cation Anion Dianion
Convince yourself that these ions fulfill Hückel’s 4n+2 rule!
Heterocyclic Aromatic Compounds
Definition: A heterocycle (heterocyclic compound) is a cyclic compound with at least
one atom other than carbon as a ring member.
Definition: A heterocyclic compound that possesses aromatic stability is called a
heterocyclic aromatic compound,
Some Examples:
N N O S
H
Pyridine Pyrrole Furan Thiophene
How do these compounds comply with Hückel’s rule?
Where are Those Lone Pairs?
Are the electron pair electrons p electrons or simple unshared pairs?
N N O S
H
Pyridine Pyrrole Furan Thiophene
Electron pairs colored in magenta are p electrons in p-orbitals.
Electron pairs in blue are simple unshared pairs in sp2 hybridized orbitals.
Some Interesting Heterocycles
N N N
Pyrrole based heterocycles with a second
heteroatom in the ring. N O S
H
Imidazole Oxazole Thiazole
H CH3
N
Cimitidine – Have an ulcer? Try this! NCN
N CH2SCH2CH2 NHCNHCH3
N S
Romantic night lights? Firefly Luciferin
HO S N CO2 H
Polycyclic Aromatic Heterocycles
Benzene fused with pyridine:
N
N
Quinoline Isoquinoline
Benzene fused with pyrrole, furan & thiophene:
N O S
H
Indole Benzofuran Benzothiophene
DNA & RNA Bases
NH2 O O
N CH3
N HN HN
N O N O N O N
H H H
Pyrimidine Cytosine Thymine Uracil
NH2 O
N N N
N N HN
N N N N
H N HN2 N H
H
Purine Adenine Guanine
Electrophilic Aromatic Substitution
We have examined substitution reactions involving alkyl benzenes and have learned
that substitution reactions generally go in good yield when the benzylic carbon atom
is the site of substitution.
Our rational for these observations is that resonance stabilizes carbocations or
radicals on the benzylic carbon atom.
Many pharmaceutically important compounds have substituted benzene rings in
their structures.
Therefore it is important that we learn how to introduce new substituents on the
benzene ring by replacing H-atoms.
Substitution Directly on the Benzene Ring
Where is the action?
A chemical reaction on a neutral molecule will generally involve attack by either
an electrophile or a nucleophile.
Which is most likely in this case?
In benzene there are two equal energy p–MO HOMOs and two equal energy p–
MO LUMOs:
p* An electrophile will remove one or more electrons from
p*2 p*3 a HOMO orbital.
p2 p3 A nucleophile will add one or more electrons to a LUMO
p
orbital.
Benzene In either case the aromatic stabilization will be lost!
What do Reactants See?
A combination of the HOMO and HOMO(-1) MOs will provide us with some indication of the
electron density available to an electrophile:
The two MOs have been colored grey simply to ignore the
phase information.
Clearly there is easy access to the p-electrons of benzene;
that is, there are not steric concerns for electrophilic attack.
Thus we might expect that a reaction with an electrophile
would take place readily.
Ar H+ E Y Ar E + H Y
Electrophilic Attack; Aromatics vs. Alkenes
+ E Y slow E
+
+ Y-
Alkene:
1. Electrophile attacks
2. Nucleophile adds
E
+
+ Y
- fast E Y
H H
Arene: slow
+E E
+
1. Electrophile attacks Y Y
2. Proton dissociates
E
H fast
+ HY
E
+ Y
E
H
Y
H
Nitration of Benzene
H H2SO4 NO2
+ HNO3 + H2O
30 – 40 ºC
What is the electrophile?
•HNO3?
•H+?
•NO3-?
•None of the above?
The electrophile is generated in situ:
HNO3 + 2H2SO4 NO2+ + H3O+ +2HSO4-
Mechanism for the Nitration of Benzene
O
+ -
H N O
O
Step1 + N+
slow
H
+
O
O
+ -
N O
H NO2
fast
Step2 +
H + O
+ H3O +
H
Sulfonation of Benzene
H SO2OH
heat
+ H2SO4 + H2O
Once again, the electrophile is not obvious in the above equation. Sulfuric acid
contains some sulfur trioxide (SO3) that is the actual electrophile. Sulfuric
acid enriched with SO3 (fuming sulfuric acid) is frequently used!
H2SO4
SO2OH
+ SO3
Mechanism for the Sulfonation of Benzene
O O-
S+
HO O-
+ slow
Step 1 + S O H
+
O-
O O- O -
S+ - + O
S
O fast
H + - OSO2OH O + HOSO2OH
-
Step 2 +
O - H OSO2OH
+ O
S SO2OH
Step 3 O- fast
+ - OSO2OH
Bromination and Chlorination of Benzene
Bromination of alkenes is carried out with molecular bromine as an electrophilic
addition reaction.
The reaction of molecular bromine with benzene is too slow to be of practical use.
However, addition of elemental iron changes things dramatically.
The chemistry:
Step 1 2 Fe + 3 Br2 2 FeBr3
An oxidation reduction reaction produces the active catalyst
+ -
Step 2 Br Br + FeBr3 Br Br FeBr3 The activated
Lewis Acid-Lewis
Lewis Lewis
Base
electrophile
Base Acid
Complex
Bromination Mechanism
Br
H
+ -
Step 1 Br Br FeBr3
slow
H +
-
FeBr4
+
1. Electrons from the arene attack the Lewis Acid-Base Complex.
2. A s-complex intermediate is formed for the arene by adding the electrophile.
Br
- Br
fast
Step 2 + H Br FeBr3 + HBr + FeBr3
1. The FeBr4 base attacks the s-complex to extract a proton
2. The aromatic (resonance stabilized) aromatic ring is regenerated.
The mechanism follows an addition (Step 1) elimination (Step 2) pathway.
Friedel-Crafts Alkylation of Benzene
H C(CH3)3
AlCl3
+ (CH3)3CCl 0 oC + HCl
Again, activation of the electrophile is the crucial step in these
reactions. t-Butylchloride is not sufficiently electrophilic to react with
benzene. AlCl3 serves as a catalyst:
(CH3)3C Cl AlCl3 (CH3)3C Cl AlCl3
+ -
(CH3)3C Cl AlCl3 (CH3)3C + AlCl4
Activated
Electrophile
The Mechanism
C(CH3)3
H H3C
Step 1 + CH slow
H
3 +
H3C
C(CH3)3
- C(CH3)3
Step 2 H Cl AlCl3
fast
+ HCl + AlCl3
+
Note the similarities in this mechanism with the bromination of benzene mechanism!
The addition-elimination pathway is seen again.
There is a serious limitation to the Friedel-Crafts alkylation reaction!
Any idea what it is?
The Limitation!
The limitation comes about because of the formation of a carbocation as the activated
electrophile.
Rearrangement must be contended with.
For example:
C(CH3)3
+ (CH3)2CHCH2Cl + HCl
A primary alkyl halide rearranges to a 3o carbocation to give t-butylbenzene.
Friedel-Crafts Acylation of Benzene
O
O
CCH2CH3
AlCl3
+ CH3CH2CCl carbon disulfide + HCl
40 oC
The active electrophile is a resonance stabilized acylium ion:
+ +
CH3CH2C O CH3CH2C O
Stable
Resonance
Form
Check out the activation of the acyl halide by AlCl3
Activation of Propanoyl Chloride
O O
- + -
+
CH3CH2C Cl + AlCl3 CH3CH2C Cl AlCl3 CH3CH2C O + AlCl4
The Mechanism
O
+
H O CCH2CH3
Step 1
slow
C H
+
CH2CH3
O O
CCH2CH3 CCH2CH3
fast
Step 2 + H Cl AlCl3 + HCl + AlCl3
To Rearrange or Not to Rearrange
The acyl cations do not rearrange:
O
+ Less stable cation;
C C O X C C
+
R
6-electrons on C
R
An alternative source of acyl cations:
O O
Carboxylic acid anhydrides
RCOCR
O
O O O
CR
+ RCOCR + RCOH
Two Step Synthesis of Alkyl Benzenes
O
O
CH2R
RCCl R Reduction
AlCl3
Reduction is accomplished with either Zn(Hg) – Zinc-Mercury Amalgam or with
hydrazine (H2NNH2) and sodium or potassium hydroxide in a high boiling alcohol such
as triethylene glycol.
Both methods are specific for reduction of aldehydes or ketones. Carboxylic acids,
double or triple bonds are not affected.
Rate and Regioselectivity in Aromatic Substitution
Does the presence of a substituent on a benzene ring influence the
addition of other substituents?
If so, what are the effects and can they be useful?
Possible effects: Rate of substitution and position of the added substituent.
Rates of electrophilic aromatic substitution are generally compared with
benzene.
An activating substituent causes subsequent substitution to be faster than that
for benzene.
A deactivating substituent causes subsequent substitution to be slower.
CH3 CF3
Toluene
(Trifluoromethyl)benzene
Reference Deactivating
Activating
Rates of Substitution and Activation Energy
Rates of reactions are governed by the energetics of the reaction pathway!
In particular a slow step in a reaction has a higher activation energy (Eact or
DEact) than a fast one.
Benzenium Ion
Intermediate
Energy
Benzene Toluene (Trifluoromethyl)benzene
An Estimate of Eact
Using ab initio calculations, a value for EHOMO can be estimated.
The program SPARTAN® was used in this case employing a
631G** basis set.
The activation for the formation of the respective cations can be
roughly approximated with the energy necessary to remove an
electron from the benzene derivative p-system.
Because of the nature of ab initio calculations comparisons of
relative energies is appropriate. In this case we will use
EHOMO for benzene as the reference.
• EHOMO for toluene is 19.05 kJ/mol higher (less negative) than
that for benzene.
• For trifluoromethylbenzene the value is 54.72 kJ/mol lower
(more negative) than that for benzene.
Graphically
DE~ 54.72 kJ/mol
DE~ -19.05 kJ/mol
Energy
Benzene Toluene (Trifluoromethyl)benzene
A Visual Comparison
The same theoretical calculations used to estimated the energy of
the HOMO also can be used to produce some visible aids to
compare the three molecules.
0.29 2.87
Toluene Benzene Trifluoromethylbenzene
•Comparison of electrostatic potential surfaces. Red is negative, blue is positive.
•Comparison of dipole moments.
Regioselectivity in Electrophilic Aromatic Substitution
The effect of a substituent on the regioselectivity of the next electrophilic aromatic
substitution as exemplified by the nitration of toluene and (trifluoromethyl)benzene:
CH3 CH3 CH3 CH3
NO2
HNO3
Acetic + +
anhydride
NO2
63% 3% NO2
34%
CF3 CF3 CF3 CF3
NO2
HNO3
H2SO4 + +
NO2
6% 91%
NO2
3%
Theory of Directing Effects
• For ortho-para directors, ortho-para attack
forms a more stable cation than meta
attack
– ortho-para products are formed faster than
meta products
• For meta directors, meta attack forms a
more stable cation than ortho-para attack
– meta products are formed faster than ortho-
para products
Theory of Directing Effects
– -NO2: assume ortho-para attack
N O2
+ N O2 + slow
N O2 N O2 N O2 N O2
+
fast
+ + - H+
H N O2 H N O2 H N O2
N O2
(d) (e) (f)
Theory of Directing Effects
– -OCH3: assume ortho-para attack
OCH3 OCH3
+ N O2 + slow
+ N O2
:
:
: OCH3
:
:
: OCH3 OCH3 : OCH3
fast
+ - H+
+ +
H N O2 H N O2 H N O2 H N O2
(d) (e) (f) (g )
Di- and Polysubstitution
– the order of steps is important
CH3 COOH
HNO3 K2 Cr2 O7
H2 SO4 H2 SO4
CH3 NO2 NO2
p-Nitrobenzoic
acid
COOH COOH
K2 Cr2 O7 HNO3
H2 SO4 H2 SO4
NO2
m-Nitrobenzoic
acid
Di- and Polysubstitution
• From the information, we can make these
generalizations
– alkyl, phenyl, and all other groups in which the
atom bonded to the ring has an unshared pair
of electrons are ortho-para directing. All other
groups are meta directing
– all ortho-para directing groups except the
halogens are activating toward further
substitution. The halogens are weakly
deactivating
Di- and Polysubstitution
Strongly
:
:
:
:
: :
activating
Ortho-para Directing
N H2 N HR N R2 OH OR
:
O O O O
Moderately
:
:
:
:
activating N HCR N HCAr OCR OCAr
:
:
Weakly
activating R
Weakly
:
:
:
: :
deactivating F: Cl : Br : I:
:
:
:
O O O O
Meta Directing
CH CR COH COR
Moderately
deactivating O
CNH 2 SO 3 H C N
Strongly
+
deactivating N O2 N H3 CF3 CCl3
Memorize!!!!!!!!