Download Advanced Organic Chemistry (Chapter 7)

Chapter 7
pK R H
[R  H]
 H   log

[R ]
Carbanions and Other Nucleophilic Carbon Species
H
O
O
O
O
Et
H3C
OEt
H3C
H3C
O
H3C
R
Li
R
H3C
R
Li + 4 (CH3)2NCH2CH2N(CH3)2
Li
Li
R
N
Tetramethylethylenediamine
(TMEDA)
H3C
O
C
C
CH3
N
CH3
Li
R
H3C
O
R
Li
N
N
CH3
CH3
OEt
7.1 Acidity of Hydrocarbons
Determination of the relative acidity of most carbon acids
is more difficult, because they are so weak acids.
Very weakly acidic solvents such as DMSO and
cyclohexyl amine are use as solvent for carbanion
generation.
Basicity constant H_: The basicity of base-solvent
system. (Analogous to the Hammett acidity function HO.
The value of H_ corresponds essentially to the pH of
strongly basic non-aqueous solutions.
The larger values of H_, the greater is the proton
abstracting ability of the medium.
Advanced Organic Chemistry (Chapter 7)
sh.Javanshir
Assignment of H_ to base-solvent system:
Use of a series of overlapping indicators.
Advanced Organic Chemistry (Chapter 7)
sh.Javanshir
Determination the acidity
hydrocarbon at a known H_ :
(pK
values)
-
-
R
pK R H
[R  H]
 H   log
[R  ]
R-H + B
of
+ B-H
If the electronic spectra of the neutral and anionic forms
are sufficiently different, the concentrations of each can
be determined directly.
Advanced Organic Chemistry (Chapter 7)
sh.Javanshir
If the electronic spectra of the neutral and
anionic forms are not sufficiently different, one
of the indicators used and its spectrum is
monitored.
-
RH + In
-
R
+ HIn
Thermodynamic Acidity: Acidity of hydrocarbons
in terms of the relative stabilities of neutral and
anionic forms.
In many cases it is not possible to obtain equilibrium
data.
kinetic Acidity: Rate of deprotonation of hydrocarbons.
Isotopic Exchange: In the presence of a source of
deuterons, the rate of incorporation of D atom into an organic
molecule is a measure of the rate of carbanion formation:
RH + B-
R- + BH
R- + S-D
R-D + S-
S- + B-H
S-H + B-
There is often a correlation between the kinetic acidity
and thermodynamic acidity.
Advantage of kinetic measurements: Not requiring the
presence of a measurable concentration of the carbanion
at any time. The relative ease of carbanion formation is
judged from the rate at which exchange occurs. This
method is therefore is applicable to very weak acids.
disadvantage of kinetic measurements: complication
due to the fate of the ion pair that is formed.
If the ion pair separates and diffuses into the solution
rapidly, so that each deprotonation result in exchange, the
exchange rate is an accurate measure in exchange.
Basis for Using Kinetic Acidity Data
Under many conditions, an ion pair may return to reactant
at a rate exceeding protonation of carbanion by the solvent
(internal return) and exchange has not been resulted.
R3C-H + M B
ionization
[R3C M
+ BH]
R3C
+ M + BH
S-D
Exchange
internal
return
R3C-D + S
An evidence for occurring internal return:
Racemization without Exchange at Chiral Center
Extent of Ion Pair or Dissociated Forms
Solvent Polarity: Ion pairing is greatest in no-polar
solvents such as ethers. In dipolar solvents , such as
DMSO, dissociated forms are predominant.
Structure: The identity of the cation present have
significant effect if ion pairs are present.
The rate of tritium exchange (kinetic acidity)
for a series of related hydrocarbons is linearly
related to the equilibrium acidities of these
hydrocarbons in the solvent system.
e.g.
Ph3CH > Ph2CH2 > PhCH3
>>
H
H
di-benzofluorene
H
H
di-benzocycloheptatriene
Allylic Conjugation:
H
pK=43 (cyclohexyl amine)
pK=47-48 (THF-HMPA)
H
H
H
H
pK=45 (cyclohexyl amine)
sp2 Hydrogens of benzene and Ethylene
Ph-H (Benzene): pK = 43
Estimated on the basis of extrapolation from a series
fluorobenzenes.
Ethylene: pK = 46
Estimated by electrochemical methods.
Saturated Hydrocarbons: Exchange is too slow
and direct determination of the pK values is not
feasible.
Measurement of the electrochemical potential for the
reaction:
-
R + e
-
R
From this value and known C-H bond dissociation
energies, pK values can be estimated (semi
quantitative method).
Isobutane: pK = 71
sp Hydrogens in Acetylenes
for
PhC
C-H
pK=26.5 (DMSO)
pK=23.2 (cyclohexyl amine)
The relative high acidity of acetylenes
associated with the large degree of s
character (50%) of C-H bond.
The sp orbital is more electronegative than
sp2 and sp3.
Ab initio calculations: CH3- and Et- have
pyramidal shape.
The optimum bond angle of H-C-H is 97-100°.
Carbanions are predicted to be pyramidal.
In planar carbanion, the LP would occupy a p
orbital.
In pyramidal geometry, the orbital would have
substantial s character.
Since, the LP would be of lower energy in an
orbital with some s character.
Stereochemistry of H-Exchange
CH3CH2
CH3
O-H
C
C
Ph
CH3
Optically Active
H
CH2CH3
Base
CH3CH2CCH3
S-H
B-H
Ph
+
CH3CH2 C CH3
CH3
CH3CH2 C CH3
O
Low dielectric constant solvents: Retention of
configuration.
Increasing the amount of inversion with increasing
the proton-donating ability and dielectric constant of
the solvent.
Base: t-BuOK
Solvent: Benzene
93% net retention of configuration
Short lifetime for the carbanion in a tight ion pair.
Carbanion does not symmetrically solvated before
protonation by H-B or ketone.
Base: KOH
Solvent: Ethylene Glycol
48% net inversion of configuration
Solvent is a good proton source and the protonation
must be occurring on an unsymmetrically solvated
species that favor back-side protonation.
Base: t-BuOK
Solvent: DMSO
100% Racemization
Sufficient lifetime for the carbanion to
become symmetrically solvated.
The Stereochemistry
2-phenyl butane:
of
H-D
exchange
in
Base: t-BuOK
Solvent: t-BuOH
retention of configuration
Ion pair formation in which a solvent molecule
coordinated to the metal ion acts as the proton donor.
Base: t-BuOK
Solvent: DMSO
Racemization
Symmetrical salvation is achieved prior to deuteration.
D
R
D
R
O
Et
Et
O
R
H3C
C
H
K+
+
R
H3C
O
D
Ph
C
K+
Ph
D
H
OR
O
D
R
R
O
Et
R
H3C
C
H
+
K+
Ph
O
D
O
H
R
O
The most preparative method of organo
lithium compounds:
CH3I + 2Li
CH3Li + LiI
n-BuBr + 2Li
n-BuLi + LiBr
PhBr + 2Li
PhLi + LiBr
Although these compounds have some covalent
character, but they react as would be expected of the
carbanions derived from simple hydrocarbons.
The order of basicity and reactivity in H-abstraction:
CH3Li > n-BuLi > t-BuLi
Deprotonation of Ph-CH3 by t-BuLi is thermodynamically
favor, but the reaction is quite slow in hydrocarbon as
solvent.
Organo lithiums exist as tetramer, hexamer and higher
aggregation in hydrocarbons and other solvents. These
species can be studied by low temperature NMR
spectroscopy.
[(BuLi)4.(THF)4] + 4 THF
major
2[(BuLi)2.(THF)4]
minor
Increasing the reactivity of organo lithiums
H3C
R
Li
R
H3C
R
Li + 4 (CH3)2NCH2CH2N(CH3)2
Li
Li
R
N
Tetramethylethylenediamine
(TMEDA)
N
CH3
Li
R
H3C
H3C
CH3
R
Li
N
N
CH3
CH3
PhLi is tetrameric in 1:2 ether - cyclohexane, but
dimeric in 1:9 TMEDA - cyclohexane.
H3CH2C
Li
Li
H3CH2C
CH2CH3
Li
Li
CH2CH3
N
tetrameri structure
(distorted cubic)
Li
N
Li
N
N
CH3
Ph
C
C
C
C
CH3
Li
CH3
Li
H3C
N
CH3
N
N
N
H3 C
2,2'Dilithiobiphenyl
(complexed with HMEDA)
Lithium phenylacetylide
(complexed with a diamine)
Ph
7.2 Carbanion Stabilized by Functional
Groups
Negative charge delocalization by functional groups
to more electronegative element cause stabilization
of the carbanion and increases the C-H bond acidity.
Order for anion stabilization:
NO2 > C=O > CO2R ≈ SO2 ≈ CN > CONR2
Both dipolar and resonance effects are involved:
H
O
C
N
C
H
O
H
O
H
O
C
C
R
S
R
C
H
O
H
R
O
H
S
C
O
H
R
C
H
O
H
C
H
C
H
O
C
N
O
H
H
O
H
C
H
H
N
C
H
C
N
S
O
R
Enolate Ions
O
OH
RCCH2R'
RC=CHR'
Keto
Enol
O
RC=CHR'
Enolate
O
RCCHR'
Measuring the kinetic Acidity of C=O Compounds:
Measuring the rate of halogenation of C=O compounds.
O
R2CHCR' + B
O
slow
O
R2C=CR' + X2
R2C=CR' + BH
O
fast
R2CCR' + X
X
Rate of Deprotonation: Isotope exchange using D or T
O
O
B
R2CHCR'
O
R2C=CR' + S-D
R2C=CR' + BH
O
R2CCR' + S
D
Rate of deuteration of simple alkyl ketones:
CH3 > RCH2 > R2CH
Steric hindrance to the approach of the base is probably
the major factor.
Structural Effects on The Rate of Deprotonation
Very strong bases such as LDA or HMDS in polar aprotic
solvents such sc DME or THF gives solutions of the enolates
whose composition reflect the rate of removal of the different
protons in the unsymmetrical C=O compounds (kinetic
control). The least hindered proton is removed most rapidly
under these conditions.
For unsymmetrical ketones the kinetic product is
less substituted one.
Thermodynamic
Control:
Establishing
the
equilibrium between the various enolates of a ketone
and formation the more stable enolate highly
substituted.
Ideal conditions for kinetic control of enolates
formation are those in which deprotonation is rapid,
quantitative, and irreversible.
Experimentally:
a) Using very strong base such as LDA
b) Aprotic solvent
c) Absence of excess ketone
d) Low temperature
Kinetic and Thermodynamic Acidity in Nitroalkanes
show opposite responses to alkyl substitution.
Umpolung Reactions: Formal reversal of the normal
polarity of a functional group.
Conjugate base of 1,3-dithiane (pK=31 in cyclohexyl amine):
S
S
H
H
+ n-BuLi
THF
S
S
H
Li
+ n-Bu-H
a) Negative charge delocalization involving 3d orbitals.
b) MOT: Negative charge delocalization involving s*
orbital of C-S bond.
Carbanion Derived from Sulfoxides
H
O
H
R'
O
R'
removed preferentially
R
R
RCHSR'
O
H
RCH2SR'
O
Phosphorous and Sulfur Ylides
Ylides: Molecules for which one of the contributing
structures has opposite charges on adjacent atoms when the
atoms have octet of electrons.
R2C
PR'3
R2C
PR'3
Phosphonium Ylide
O
R2C
O
SR'2
R2C
SR'2
Sulfoxonium Ylide
R2C
SR'2
Sulfonium Ylide
R2C
SR'2
Formation of Ylides
Deprotonation of onium salts:
RCH2
base
PR'3
PR'3
Phosphonium Ylide
Phosphonium Salt
R'2SCH2R
RCH
base
Sulfonium Salt
R'2S
CHR
Sulfonium Ylide
O
O
base
R'2S
CH2R
Sulfoxonium Salt
R'2S
CHR
Sulfoxonium Ylide
The stability of the resulting species is increased by
substituents groups that can help to stabilize the electronrich carbon. In the absence of any stabilizing group, the
onium salts are much less acidic and strong bases such as
amide ion is required.
RCH2
PR'3
strong
base
RCH
PR'3
O
O
base
R'2S
CH2R
Sulfoxonium Salt
R'2S
CHR
Sulfoxonium Ylide
The addition of O atom in the sulfoxonium salts stabilizes
these ylides considerably relative to the sulfonium ylides.
7.3 Enols and Enamines
Carbonyl compounds as nucleophile in acidic media:
Enol form:
O
OH
RCCH2R + H+
OH
RC=CHR + E+
OH
RC=CHR + H+
RCCH2R

OH 
O
OH
RC

CH2R
RC CH2R

E
E
Enols are not as reactive as enolate ions.
RC CHR + H+
E
Enolization Mechanism: Isotope Exchange
O
OH
H
fast
+ HA
OH
A
slow
+ HA
kH / kD ≈ 5
Measuring The Rate of Enolization: Halogenation
O
RCCH2R
k1
HA
k-1
OH
RC=CHR
k2
X2
fast
k2 >> k-1, k-1
O
RC CHR + HX
X
In contrast with base catalyzed removal of proton, the
acid catalyzed enolization to result in preferential
formation of the more substituted enol.
The amount of enol present in equilibrium with a
C=O group is influenced by other substituents
groups. In single ketones, aldehydes, or esters, there
is very little of the enol present at equilibrium.
H
H3C
O
O
C
C
C
H
O
CH3
H3C
H
O
H
CH3
Effect of Solvent on the Extent of Enol Form
Ethyl acetoacetate:
H
O
O
O
O
Et
H3C
OEt
H3C
H3C
O
Solvent
Enol form (%)
CCl4
15-20
Acetone
5
Water
1
O
O
C
C
OEt
The strong intramolecular H-bond in the enol form minimize
the molecular dipole by reducing the negative charge on the
oxygen of the C=O group.
In the more polar solvents is less important, and in protic
solvent such as water, H-bonding by the solvent is dominant.
Generation of Enols of Simple Ketones in high
Concentration: Metastable species
H
RCO2C
OCH=CH2
H2O, CH3CN
-20 °C
RCOOH + HCOOMe + HO-CH=CH2
OCH3
NMR: Half life at -20 °C is several hours
Half life at +20 °C is 10 minutes
In DMSO and DMF, in which the rate of exchange by
H-binding is slow, metastable enols have increased
lifetime.
Generation of Enols of Simple Ketones in Water:
Addition of enolate solution to water: The initial
protonation takes place on O atom, generating the enol
form. Ketonization rate depends on pH.
Acid Catalyzed Ketonization: C-protonation concerted
with O-deprotination (General acid catalysis)
H
H2O
O
O
H
C
H
HA
C
HCCH3 + H3O
+ A
H
Base-catalyzed Ketonization: C-protonation of the enolate
H
O
C
H
O
H
C
C
+ B
H
H
H
C
H
H2O
O
C
H
CH3 + OH
Enols are more acidic than ketones
O
O
Ph
CH3
H3C
K=10-18.4
K=10-7.9
OH
O
CH2=CPh
CH2=CPh
K=10-10.5
CH3
K=10-19.2
K=10-9.2
O
OH
CH2=CCH3
CH2=CCH3
K=10-11
Enamines
R2N
R
C
R
R2N
R
C
C
R
enamine
C
R
R
imine
Enamines of 2-Alkylcyclohexanones
CH3
CH3
N
H
Steric Repulsion
N
Strongly Favored
Preference for the formation of less substituted isomer.
H
R
H
H
N
H
H
R
N
H
favored
disfavored
7.4 Carbanions and Nucleophiles in SN2
Reaction
Carbanions are soft nucleophiles.
Evidences for SN2 type mechanism:
Reaction of 2-bromobutane: a) Allyl and benzyl lithium
Complete inversion of configuration
b) BuLi
Racemization
Complicating process: the reaction of organo lithium
reagents with alkylating reagents conceivably occur at
any of the aggregation stages present in solution.
(RLi)4
R'X
R-R'
2(RLi)2
4 RLi
R'X
R'X
R-R'
R-R'
*
Cl
*
Ph-Li + Cl-CH2CH=CH2
Li
*
Ph-CH2CH=CH
2
*
*
Ph-Li + Cl-CH2CH=CH2
Cl
Li
Li
*
Ph-CH2CH=CH2
Alkylation of Enolate Ions: C-Alkylation vs.
O-Alkylation
O
O
Soft electrophiles prefer C-alkylation.
O
HOMO of enolates have p-character: Attack of
electrophile approximately perpendicular to the plane of
the enolate.
X
X
X
O
O
O
Both tetrameric and dimeric clusters can exist.
Sensitivity of the reaction rate to the degree of
aggregation.
a) Addition of HMPA, crown ethers or similar complexing
agents:
The rate acceleration of enolate alkylation reaction.
b) Use of dipolar aprotic solvents (e.g. DMF, DMSO in
place of THF):
The rate acceleration of enolate alkylation reaction.
c) Effect of metal cation: Reactivity order
BrMg+ > Li+ > Na+ > K+
According the order of dissociation of ion pair and
aggregates.
C- versus O-alkylation
a) Addition of HMPA, crown ethers or similar
complexing agents:
Increasing the O-alkylation product.
b) With the soft leaving groups such as Br- and IC-alkylation is the major pathway.
Steric and Stereo electronic Effects
Enolates that are exocyclic to cyclohexane ring:
axial
X
-
O
equatorial
Preference for equatorial attack.
Endocyclic cyclohexanone Enolates that are to ring.
less
favorable
R'X
R'
H
H
R
t-Bu
O
O
O
t-Bu
R
R'
t-Bu
R'X
more
favorable
The Enolates of 1-Decalone.
favored
R'X
H
H
R'
OO
disfavored
END OF CHAPTER 7