The Hammett Equation And The Curtin-Hammett Principle

Simon Meek LT1, 5pm 4/4/2005

S. J. Meek

Louis P. Hammett (1894-1987); David Y. Curtin (1920- )

The Hammett Equation log K = sr K0 Curtin-Hammett Principle log k = sr k0

PA

k1 Slow

kA kB Fast

k2 Slow

PB

k1, k2 << kA, kB

S. J. Meek

Linear Free Energy Relationships

OH k
3

RCO2Et

RCO2

EtOH

2.5

RCO2H

H2O

RCO2Et

1.5

RCO2

H2O

log k

0.5

Such relationships were first studied on a thorough basis by Hammett in the1930s. Plotting log k for the reaction of esters against log K for ionisation of acids resulted in a reasonable straight line.

-0.5

-1

-1.5 -5 -4.8 -4.6 -4.4 -4.2

log K

-4

-3.8

-3.6

-3.4

-3.2

-3

RCO2H

Equilibrium constants, K, and rate constants, k, are each related to the free energy changes in the relevant reactions in the following way:
log K = -DG 2.303 RT
log k = -DG 2.303 RT + log k' T h

k' = Boltzmann's constant h = Planck's constant

S. J. Meek

Linear Free Energy Relationships

OH k
3

RCO2Et

RCO2

EtOH

2.5

ArCO2Et

RCO2H

H2O

1.5

RCO2

H2O

log k

0.5

The straight line relationship between log k for the reaction of esters and log K for ionisation in water of the corresponding carboxylic acids, implies there is a relationship between DG the free energy of activation for the ester reaction and DG the standard free energy change of ionisation in water of the acids. The straight line correlation between the free energy terms for two different reaction series are referred to as linear free energy relationships.
log K = -DG 2.303 RT
log k =

-0.5

-1

-1.5 -5 -4.8 -4.6 -4.4 -4.2 -4 log K

ARCO2H

-3.8

-3.6

-3.4

-3.2

-3

-DG 2.303 RT

+ log

k' T h

k' = Boltzmann's constant h = Planck's constant

S. J. Meek

Hammett Equation

Probably the most common linear free energy relationship. Hammett reported the Linear correlations between the logarithms of rate constants for reactions of meta- and para-substituted phenyl derivatives (logkx) and pKa values of the corresponding substituted benzoic acids.
O X OH H2O K X O O H3O
3 2.5

O X OEt H2O

log k

EtOH

ArCO2Et

NaOH EtOH

1.5

0.5

-0.5

log k = r log K + c

-1

-1.5 -5 -4.8 -4.6 -4.4 -4.2 -4 -3.8 -3.6 -3.4 -3.2 -3

log K

ARCO2H

S. J. Meek

Hammett Equation

In 1937 Hammett presented the equation:

log k = sr k0

or

log K = sr K0
Equilibria equation: effect of substituents on final state vs initial state

Kinetics equation: effect of substituents on transition state vs initial state

k = rate constant (XH) k0 = rate constant (X=H) K = equilibrium constant (XH)

K0 = equilibrium constant (X=H) s = Hammett substituent constant r = Hammett reaction constant

Hammett, JACS, 1937, 59, 96.

S. J. Meek

Derivation of the Hammett Equation

3

y = mx + c
Eq 1. log kx = r log Kx + c
ArCO2Et

2.5

1.5

log k

Considering the unsubstituted carboxylic acid R=H as the standard reaction: Eq 2. log kH = r log KH + c Subtract 2 from 1:

0.5

-0.5

-1

logkx - log kH = r(log Kx - log KH) Which can be written in the form:
log kx = r log Kx = rsx kH KH

-1.5 -5 -4.8 -4.6 -4.4 -4.2 -4 -3.8 -3.6 -3.4 -3.2 -3

log K

ARCO2H

sx :

sx = log Kx KH

or

sx = log Kx - log KH = [(-pKa(x)) -(-pKa(H))] = pKa(H) - pKa(x)

The ionisation of m- and p-benzoic acids in water (25 oC) is defined as the standard reference reaction with the reaction constant r = 1.

S. J. Meek

Hammett Equation

The Hammett relationship only applies to systems where the substituents are attached to the reaction centre via aromatic rings and are situated meta- or para-. Ortho- substituted aromatic rings do no fall on the line owing to steric and through-space effects. ie.increased crowding in the tetrahedral intermediate Aliphatic acids do not fall on the line, due to a small Increase in steric crowding in the transition state and their increased flexibility may decrese correlation between the transition state structure and equilibrium position.

2.5

p-NO2 m-NO2

1.5

1 p-I
log k/ko

p-Br p-Cl

0.5

0 -0.8 -0.6 -0.4 -0.2 p-Me -0.5 p-OMe -1

0H

0.2

0.4

0.6

0.8

p-NH2

-1.5

-2 log K/Ko

OH OEt

OH OEt

= o-substituent

= aliphatic

S. J. Meek

Hammett Substituent Constant s

The substituent constant (s) for meta- and para-substituents in benzene derivatives as defined, on the basis of the ionization constant of substituted benzoic acid in water at 25 oC. ie. X=H s is a collective measure of the total electronic effects of a substitutent [resonance and inductive effects]. ie. how electron withdrawing or donating a substituent is in its ability to supply/withdraw electrons to/from the reaction site. s is independent of the nature of the reaction site. s is defined separately: sm for meta-substituents sp for para-substituents
O OH X
para-: strong conjugation into carbonyl meta-: conjugation into ring not carbonyl balances weak effect of X

O X OH

Inductive effect: caused by polarization of the s-bonds. sm > sp for a given substituent due to its closer proximity to the reaction site. Resonance effect: conjugation is stronger for p-substituents than meta-. sp > sm for a given substituent

S. J. Meek

Physical Meaning of s

Magnitude of s: larger +/-values= greater inductive and/or conjugative effect of substituent. s is -ve = electron-donating s is +ve = electron-withdrawing s = 0, substituent has no effect (ie. electronically the same as X=H)
O O2N OEt OH km-NO2 RDS O2N d-O dOH d- OEt O O2N OH OEt

Recall: sx = pKa(H) - pKa(x)

km-NO2 KH = 63.5

sm-NO2 = +0.71
O Me OEt OH km-Me RDS Me

transition state d-O dOH d- OEt

tetrahedral intermediate O Me

OH OEt

km-Me KH

Electron-withdrawing m-NO2 increases stability of tetrahedral intermediate cf. to electron-donating m-Me

= 0.66

sm-Me = -0.07
O MeO OEt OH km-OMe MeO RDS

transition state

tetrahedral intermediate

d-O dOH d- OEt

O MeO

OH OEt

km-OMe > kH

sm-OMe = +0.12
O OEt MeO OH kp-OMe RDS MeO

transition state

tetrahedral intermediate

d-O dOH d- OEt MeO transition state

OH OEt

kH > km-OMe

OMe can be electronwithdrawing in the metaposition due to inductive effects or electron-donating in the para-position due to a conjugative effect

sp-OMe = -0.27

tetrahedral intermediate

S. J. Meek

Hammett Reaction Constant r

The constant of proportionality between log k (or K) and s values The magnitude of r reflects how sensitive a particular reaction is to the electronic effects of the substituents. Sign of r (the slope) shows whether a reaction is accelerated by EW-/EDsubstituents: -positive r: A result of the build up of negative charge at the reaction centre in the transition state of the rate determining step (rds). \ rate will be accelerated by electron-withdrawing substituents. -negative r: A result of the build up of positive charge at the reaction centre in the transition state of the rate determining step (rds). \rate will be accelerated by electron-donating substituents. NB. rate will be retarded by the opposing EW-/ED-substituent .

S. J. Meek

Standard Hammett Equations

Ionisation of para-substituted benzoic acids:

CO2H X sp = log r=1 K(pXC6H4CO2H) K(C6H4CO2H) K X , at 25 oC in aqueous solution CO2 H

Ionisation of meta-substituted benzoic acids:

X CO2H K X CO2 H

sm = log r=1

K(mXC6H4CO2H) K(C6H4CO2H)

, at 25 oC in aqueous solution

S. J. Meek

Through-conjugation

In many cases a breakdown in linearity between log Ks and ss is observed for strongly EW-/ED-substituents as predicted by the Hammett relationship. Example: ionization of phenols and anilines
OH X H2O X O H3O
log Kx KH

.
p-CN, p-NO2

(XC6H4OH)

p-CN, p-NO2 substituted phenols are stronger acids than would have predicted by the Hammett correlation. ie. values lie above the line

. .

log Kx KH

(XC6H4CO2H)
H N O N O

NH2 O

Reason: resonance stabilization can be extended through to the reaction centre by throughconjugation more stabilized species.
O

N O

OH N O O N O

S. J. Meek

Through-conjugation: sx- and sx+

Through-conjugation effects can be separated from the inductive effects to produce new s-values which account for through conjugation non-linearity. A Hammett correlation with r based on m-substituents only can be developed (NB. m-substituents do not exhibit a resonance effect directly to the reaction centre). The amount by which certain substituents deviate from the line can be added or subtracted from their s-values to produce sx- and sx+ modified substituent constants.
log Kx KH

p-NO2 p-CN

sx- strongly electron-withdrawing groups

Substituent
(in XC6H4OH)

(XC6H4OH)

sp 0.45 0.50 0.66 0.43 0.78

sp0.68 0.84 0.88 1.03 1.27

CO2Et COMe CN CHO NO2

log Kx KH

(XC6H4CO2H)

S. J. Meek

Through-conjugation: sx- and sx+

sx+ strongly electron-donating groups

log kx kH
p-MeO p-Me

Substituent C6H5 Me MeO NH2 NMe2

sp -0.01 -0.17 -0.27 -0.66 -0.83

sp+ -0.18 -0.31 -0.78 -1.30 -1.70

sx
Caveat: Choosing between s, s- and s+ presupposes the mechanism of the reaction. SNAr reactions correlate well with s-; SEAr reactions correlate well with s+.

S. J. Meek

Through-conjugation: sx- and sx+

sx+ reference reaction: solvolysis of cumyl chlorides

X k(XC6H4C(CH3)2Cl k(C6H4C(CH3)2Cl Cl X Cl

sx+ = log r=1

, at 25 oC in 90% aqueous acetone

sx- reference reaction: ionisation of substituted phenols

sx- = log r=1 Ka(XC6H4OH) Ka(C6H5OH)

OH X X

, at 25 oC in aqueous solution

S. J. Meek

Typical Hammett Plot & Summary of r-values

r= +ve: electrons flow towards the aromatic ring in the RDS r= -ve: electrons flow away from the aromatic ring in the RDS
s = -ve EDG: MeO, Me, NH2,..

Log k

s
s = 0.0 X=H

s = +ve EWG: Cl, CO2Et, CN, NO2,..

r:
-6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6

Large -ve: +ve charge on ring or delocalized round benzene ring

Moderate -ve: flow out of TS +ve charge in near ring loss of conjugation e-s

Small r: Moderate +ve: Large +ve: -s flow into TS 1.Ar too far away e -ve charge on - change 2.No e -ve charge in near ring ring or 3. Two r-values loss of conjugation delocalized cancel each other round benzene out ring

S. J. Meek

Uses of the Hammett Equation

Calculation of k or K for a specific reaction of a specific compound (This is limited to substituted arenes). s-values for substituents are known
log kx = rsx kH

Provided r is known for the specific reaction, the rate (or equilibrium) constant for any substituent relative to the unsubstituted compound can be calculated. Use r to determine information about reaction pathways: Magnitude and sign of r development of charge at reaction centre If sx- or sx+ give a better correlation than s through conjugation is important Deviations from linearity: Hammett plots are most informative at the point at which they deviate from linearity with the greatest information being found in whether they deviate concave upwards or downwards.

S. J. Meek

Deviations From Linearity

Concave upwards: Compare the plots for the hydrolysis of ArCO2Me and ArCO2Et carried out in 99.9% H2SO4.
ArCO2Me

log kx

r = -3.25

Me shows expected correlation r= -3.25 Mechanism:

O H OMe Ar O OMe H -MeOH RDS O Ar H O 2 Ar O OH H H2O Ar O OH Ar

ArCO2Et

r = -3.25

r +2.0

-positive charge develops in RDS and reaction is accelerated by ED-substituents.

sx

Et esters show an expected correlation r=-3.25 switching to r=+2.0. Change in mechanism: -Et esters can form a more stable carbocation, O O RDS O CH2CH3 +CH2CH3 (cf. Me esters) n.b.essentially under Ar OEt Ar O Et Ar OH anhydrous conditions H H - EW-substituents decrease the positive charge at the reaction centre in the rate RDS and accelerate the reaction

S. J. Meek

Deviations From Linearity

O Ar H2O Cl acetone Ar O OH

Concave Upwards: Hydrolysis of acid chlorides.

O Ar Cl -Cl RDS
r = -4.4

O Ar H O 2 fast
log kx
ArCO2Cl

O
RDS

Ar H2O

Cl

r = +2.5

O Ar OH

fast Ar

O OH H OH2
r = -4.4 r = +2.5

sx

Mechanism 1(SN1): rate is accelerated by ED-substituents

Mechanism 2: rate is accelerated by EWsubstituents

Concave upwards deviation: Indicates a change in reaction mechanism -any new pathway occurring must be faster than the original for it to become dominant -curving upwards of the correlation means the new mechanism is faster

S. J. Meek

Deviations From Linearity

Concave Downwards: Intramolecular Friedel-Crafts alkylation

H2SO4 OH Ph H2O, HOAc Ar Ph

log kx
r=+2.67 r=-2.51

Ar

+ve r for ED-substituents -ve r for EW-substituents

H OH Ph Fast Ar Ph OH2

s=+0.5 EWG -s E1 SEAr

Ph Ar H Ph -H Fast

sx EWG +s

Ar

RDS?

RDS?

Ar

Ar

Ph

Which step is RDS? - E1: a positive charge is increasing at the reaction centre (-ve r) \ E1 is RDS for EW-substituents (ie. RDS for right-hand of Hammett correlation ) - SEAr: positive charge at the reaction centre is decreasing (+ve r) \ SEAr is RDS for ED-substituents (ie. RDS for left-hand of Hammett correlation )

S. J. Meek

Deviations From Linearity

Deviation Concave Upwards: - Indicates a change in the reaction mechanism. Deviation Concave Downwards: - Indicates the same mechanism but a change in the rate determining step.

S. J. Meek

Other Variants of the Hammett Equation

Yukawa-Tsuno Equation: introduces a further parameter into the Hammett equation to quantify the graded response to through-conjugation for para-substituents.
s+ for electron-donating p-substituents s- for electron-withdrawing substituents r = a measure of through conjugation operating in a particular reaction

kx log = r[sx +r(sX+-sx)] kH

r = 1.0 for the solvolysis of tertiary halides eg. cumyl chloride If no through-conjugation occurs r=0 and the equation simplifies to the original Hammett equation Base-catalysed hydrolysis of p-phenoxytriethylsilanes gives r=0.50 The extent of through conjugation by a group such as p-NO2 gives r=+3.52 suggesting the build up of substantial negative charge in the transition state.
OSiEt3 OH + Et3SiOH X X O

dOH SiEt3 O dr =+3.52 r = 0.50 O N O

Cl

d--

d++ CMe2 r = -4.52 r = 1.0 (by definition) OMe

S. J. Meek

Other Variants of the Hammett Equation

Taft Equation: used to explain the reactivities of aliphatic esters.

log

kR = r*sR* + dEs kMe

sR* = the polar substituent constant Es = steric substituent parameter r* = measures the reactions susecptibility towards polar effects d = a measure of a particular reactions susecptibility towards steric effects (ie d is the steric parallel to r*)

d = 1.00 for acid catalysed ethylester hydrolysis Es = 0 for R = Methyl

log kRCO2Et = Es kMeCO2Et
acid

S. J. Meek

Curtin-Hammett

How does the conformation of a molecule affect its reactivity? Consider:

13MeI

Me N

Me

13MeI

Do the two different conformers react at the same rate, or different rates? What factor determines product distribution? The Situation: Consider the two interconverting conformers A and B, each of which can undergo a reaction resulting in two different products, PA and PB.
PA k1 A kA kB B k2 PB

Two limiting cases: 1. 2.

major

minor

The rate of reaction is faster than the rate of conformational interconversion The rate of reaction is slower than the rate of conformational interconversion

S. J. Meek

Curtin-Hammett

Case 1: (Kinetic Quench) The rate of reaction is faster than the rate of conformational interconversion k1,k2 >> kA,kB. If the rates of reaction are faster than the rate of conformational interconversion, A and B cannot equilibrate during the course of the reaction, and the product distribution (PA/PB) will reflect the initial composition.

PA

k1

kA kB

k2

PB

Energy

[PB]
DG1 PA A DGAB DGo B

[PA]
DG2 PB

[B]o [A]o

In this case, the product distribution depends solely on the initial ratio of the two conformers

Rxn. Coordinate

S. J. Meek

Curtin-Hammett

Case 1: (Kinetic Quench) The rate of reaction is faster than the rate of conformational interconversion k1,k2 >> kA,kB. Example:
Me less stable Me H N Me O -78 oC DG = -3.0 kcal/mol (by by ab initio calc.) Me minor product Me N O Me Me N O Me
Padwa, JACS, 1997, 4565

Me more stable

H O MeBr Me

MeBr

major product

In the case above while enolate conformers can be equilibrated at higher temperatures, the products of alkylation at -78 oC always reflect the initial ratio of enolate isomers.

S. J. Meek

Curtin-Hammett

Case 2: (Curtin-Hammett conditions) The rate of reaction is slower than the rate of conformational interconversion kA,kB >> k1,k2.

If the rates of reaction are much slower than the rate of conformational interconversion, (DGAB is small relative to DG1 and DG2), then the ratio of A to B is constant throughout the course of the reaction.

Energy

DG1 A DGo PA

DGAB

DG2

PA

k1 Slow

kA kB Fast

k2 Slow

PB

PB B

major

Rxn. Coordinate

minor

S. J. Meek

Curtin-Hammett

The Derivation: (Case 2) Using the rate equation

d[PB] d[PA]
d[PA] = k1[A] dt

and

d[PB] = k2[B] dt

we can write:

k2[B] k1[A]

or

d[PB] =

k2[B] d[PA] k1[A]

Keq = [B] [A]

Since A and B are in equilibrium, we can substitute

d[PB] =

k2 K k1 eq

d[PA]

Integration gives

[PB] [PA]

k2 K k1 eq

When A and B are in rapid equilibrium, we must consider the rates of reaction of the conformers as well as the equilibrium constant when analyzing the product ratio.

S. J. Meek

Curtin-Hammett

To relate this quantity to DG values, recall that DGo = -RT ln Keq or Keq = e-DGo/RT, k1 = e-DG1/RT, and k2 = e-DG2/RT. Substituting this into the previous equations:
[PB]
-DG2/RT k2 e -DGo/RT -DG /RT -DGo/RT -DG1/RT = k Keq = = e 2 e e e [PA] 1 -DG1/RT e

Combining terms:
[PB] [PA] = e
-(DG2 + DGo - DG1 )/RT

or

[PB] [PA]

= e

-DDG /RT

R = 8.314 J/Kmol = 2 cal/Kmol

Curtin-Hammett Principle: The product composition is not solely dependent on relative proportions of the conformational isomers in the substrate; it is controlled by the standard Gibbs energies of the respective transition states.

S. J. Meek

Curtin-Hammett

Three Senarios: If both conformers react at the same rate, the product distribution will be the same as the ratio of conformers at equilibrium. If the major conformer is also the faster reacting conformer, the product from the major conformer should prevail, and will not reflect the equilibrium distribution. If the minor conformer is the faster reacting conformer, the product ratio will depend on all three variables, and the observed product distribution will not reflect the equilibrium distribution. \ You can potentially isolate a product which is derived from a conformer you cannot observe in the ground state.

S. J. Meek

Curtin-Hammett: Examples
13Me

Me N
13MeI

Me N

Me

Me
13MeI

13Me

Faster major product

Slower less stable

JOC 1974 319

more stable

minor product

The minor conformer reacts much faster than the more stable conformer
t-Bu Me N less stable slower k1 H2O2 Me N O ratio= 5 : 95
Tet. 1972 573 Tet. 1977 915

t-Bu Keq=10.5

Me faster

more stable H2O2 k2 O N

minor product

t-Bu

t-Bu

Me

major product

S. J. Meek

Curtin-Hammett: Example
O OMe H2 (R)-BINAP-Ru OH O OMe

Stereoselective Hydrogenation:
O 99:1 92 % ee 100% yield

Why is the yield >50% ? A diastereospecific rection should not exceed 50%

- Enantioselectivities are the same , regardless of whether the starting material is already enantiomerically enriched in the opposite enantiomer. - Explanation: Enantiomerisation of the starting material through an achiral ester enolate (by tuning Lewis acidity of the solvent) is faster than the rate of hydrogenation. - This is a case of Dynamic Kinetic Resolution: Two enantiomeric keto-esters are equilibrating during the course of a reaction with H2.
O O O OMe achiral ester enolate O O OMe H2 (R)-BINAP-Ru fast
Noyori JACS 1989 111 9134

O OMe

H2 (R)-BINAP-Ru slow

OH O OMe syn OH O OMe anti

Configuration: - C-3 is governed by the handedness of the BINAP. - C-2 is dependent on substrate structures
P X P Ru H O

OMe H

S. J. Meek

Curtin-Hammett: Example

Asymmetric Hydrogenation of prochiral olefins, catalysed by Rhodium

MeO2C NHAc Ph [L2*Rh]+ MeO2C NHAc Ph

> 95% ee

chelating diphosphine ligands give very high enantioselectivities (e.g. S,S-CHIRAPHOS)

Two diastereomeric Rh-substrate complexes are formed when the chiral ligand (S,S-CHIRAPHOS), rhodium and substrate are mixed.
MeO2C NH HN CO2Me P P

A minor complex

*
P

Rh O

Ph Me Me

Ph O

Rh

B major complex

Observations: Complex B is the only observed diastereoisomer for the catalyst-substrate complex (1H-NMR, X-ray crystallography) The observed enantiomer of the product is derived exclusively from the minor complex A The enantioselectivities are dependent on the pressure of H2

S. J. Meek

Curtin-Hammett
HN CO2Me P P

Explaination: The Curtin-Hammett Principle

P

*
P

SH Rh S

MeO2C

NHAc

KBeq

Ph O Ph Me

Rh

H2 Addition is slow (S)-Enantiomer k1[H]

KAeq

B major complex

MeO2C

NH

A minor complex

*
P

Rh O

Ph Me

KAeq , KBeq > k2[H2], k1[H2] k2[H2] >> k1[H2]

The minor diastereoisomer complex is 580-fold more reactive than the major diastereoisomer complex 96% ee
Halpern JACS 1987 109 1746

H2 Addition is fast

k2[H]

*
H P

MeO2C P Rh O H

NH

migration +S
Me

*
H P

P Rh S O

CH2Ph CO2Me

reductive elimination -L2RhS2

MeO2C

NHAc

Ph

(R)
Ph

NH

Me

96% ee

S. J. Meek

Curtin-Hammett

Curtin-Hammett Principle: The product composition is not solely dependent on relative proportions of the conformational isomers in the substrate; it is controlled by the difference in the standard Gibbs energies of the respective transition states.
References Hammett Equation: 1. A guide book to Mechanism in Organic Chemistry, Peter Sykes pg358-395(sixth edition) 2. Advanced Organic chemistry: Part A, Carey, and Sundberg pg204-215 (fourth edition) 3. Free energy relationships in organic and bio-oragnic chemistry, A. Willliams, pg17-54 4. Organic Chemistry, Clayden, Greeves, Warren and Wothers. pg 1090. 4. A review of Hammett substituent constants Chem. Rev. 1991, 91, 165. The Curtin-Hammett Principle: 1. 2. 3. 4. Advanced Organic chemistry: Part A, Carey, and Sundberg pg215-261 (fourth edition) Seeman, Chem. Rev. 1983 83 83 Seeman, J. Med. Ed. 1986 63 42 Prof. D. A. Evans Chem 206 lecture 7

S. J. Meek

Questions

1. The pKa of p-methoxybenzoic acid is 4.49; that of benzoic acid is 4.19, caculate for s for p-MeO? 2.The base-catalysed hydrolysis of ethyl m-nitrobenzoate is 63.5 times faster than the unsubstituted ester under the same conditions; what will be the comparable rate of hydrolysis of ethyl p-methoxybenzoate? [From tables sm-NO2=0.71 and sp-MeO=-0.27] 3.
HO Me Ti(OiPr)4 tBuOOH, rt Product

Draw the major/minor products expected from this reaction?

The theoretical transition state energy DDG = -1.43 kcal/mol, and experimentally the product ratio = 91:09. Determine whether this reaction obeys the Curtin-Hammett principle by calculating the expected ratio of products based on the theoretical DDG value? 4. In the following B and C are diastereoisomers:
A reagents 80
oC

+ C

Assuming the diastereomeric excess is 99% de (B:C) calculate the difference in transition state energies (kcal/mol) leading to the products?

S. J. Meek

Questions

5. Use the proportion of enolates shown for the two cases (R=t-Bu and R=Et) to determine the difference in the free energies of activation at -78 oC, assuming that enolate formation is kinetically controlled?
O R O LDA, THF -78 oC R = t-Bu R = Et R 98% 30% Li R 2% 70% O Li

6. Fill in the following table and draw energy diagrams to illustrate each situation?
PA k1 A Keq B k2 PB

Keq 10-1 10+1

PB/PA 5:1 5:1

k2/k1 ? ?

DDG ? ?

7. For the Asymmetric Hydrogenation of prochiral olefins, catalysed by Rhodium (see slide 35) calculate the difference in the free energies of activation at 298K of the two diastereomeric rhodium-substrate complexes?

S. J. Meek

Questions

8. In a recent paper the following kobs were recorded for the 2-arylpyrrolidinone-catalysed aqueous aldol reaction shown below. From these values calculate r? What does r tell you about the RDS and how the various substituents affect catalysis? (note that the substituents in the table are on the Ar-group on the catalyst).

S. J. Meek

Answers

1.

The pKa of p-methoxybenzoic acid is 4.49; that of benzoic acid is 4.19, caculate for s for p-MeO?

sx = pKa(H) - pKa(x) \ sx = 4.19 - 4.49 \ sx = -0.3

2.The base-catalysed hydrolysis of ethyl m-nitrobenzoate is 63.5 times faster than the unsubstituted ester under the same conditions; what will be the comparable rate of hydrolysis of ethyl p-methoxybenzoate? [From tables sm-NO2=0.71 and sp-MeO=-0.27] For m-nitrobenzoate, Using log k = sr, where ko k = 63.5 ko

\ log(63.5) = r x 0.71 \ r = 2.5391 For p-methoxybenzoate \ \ log k = -0.27 x 2.5391 k0 k = 0.206 ko

S. J. Meek

Answers
HO Me Ti(OiPr)4 tBuOOH, rt Product

3.

Draw the major/minor products expected from this reaction?

The theoretical transition state energy DDG = -1.43 kcal/mol, and experimentally the product ratio = 91:09. Determine whether this reaction obeys the Curtin-Hammett principle by calculating the expected ratio of products based on the theoretical DDG value?
Me HO O HO H O H Major Me Minor

Using DDG = -RTln[Pb] [Pa] [Pb] = 11 \ transition state ratio = 92:08 and therefore, [Pa] agrees with the Curtin-Hammett principle.

4. In the following B and C are diastereoisomers:

A reagents 80
oC

+ C

Assuming the diastereomeric excess is 99% de (B:C) calculate the difference in transition state energies (kcal/mol) leading to the products? B : C ratio, 99.5 : 0.5 [Pb] = 99.5/0.5 = 199 [Pa] T = 273 + 80 = 353 K DDG = -RTln[Pb] DDG = -(2x10-3)(353) ln199 [Pa] = -3.7 Kcal/mol

S. J. Meek

Questions

5. Use the proportion of enolates shown for the two cases (R=t-Bu and R=Et) to determine the difference in the free energies of activation at -78 oC, assuming that enolate formation is kinetically controlled?
O R O LDA, THF -78 oC R = t-Bu R = Et R 98% 30% Li R 2% 70%
k1

Li

[Pb]/[Pa] = 49 \ DDG= -(195x1.98) ln49 -1.5 [Pb]/[Pa] = 0.43 \ DDG= -(195x1.98) ln0.43 0.33
Keq k2

6. Fill in the following table and draw energy diagrams to illustrate each situation?
PA A B PB

Keq 10-1 10+1

PB/PA 5:1 5:1

k2/k1 50 0.5

DDG -RTln5 -RTln5

7. For the Asymmetric Hydrogenation of prochiral olefins, catalysed by Rhodium (see slide 35) calculate the difference in the free energies of activation at 298K of the two diastereomeric rhodium-substrate complexes? 96 % ee ratio 98 : 2 T = 273 + 25 = 298 K [Pb] = 98/2 = 49 DDG = -RTln[Pb] DDG = -(2x10-3)(298) ln 49 [Pa] [Pa] -2.3 Kcal/mol 8. r = 1.14 (JOC 2005 70 3705)