Hammett Correlations and Their Applications in Elucidating Reaction Mechanism

Stoltz Group Literature Seminar Eric Ferreira July 17, 2003 at 12pm Ph N Yn H HN Ph OH2 NH2 O Yn Ph H

k1
Yn

k2

3.3 3.2 3.1 3

unsub

m-OMe p-Cl m-Cl

log kob s 2.9

2.8 2.7 2.6

p-Me

m-Me m-NO2

p-OMe

2.5 -0.4

-0.2

0.2

0.4

0.6

0.8

Outline & References

Outline:
- The development of the Hammett equation - Significance of ! and " - Cationic and anionic cases - Substantial deviations from correlations - More sophisticated models for quantitative analysis - Mechanism of organometallic reactions

Key References:
Isaacs, N. Physical Organic Chemistry; Wiley: New York, 1995; Ch. 4. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165. (tons of values) Jaffe, H. H. Chem. Rev. 1953, 53, 191. Lowry, T. H.; Schuller Richardson, K. Mechanism and Theory in Organic Chemistry; Harper and Row: New York, 1987; pp 143-159. Exner, O. The Hammett Equation. In Advances in Linear Free Energy Relationships; Chapman, N. B. and Shorter, J., Eds.; Plenum Press: London, 1972; Ch. 1. March, J. Advanced Organic Chemistry; Wiley: New York, 2001; pp 368-375.

The First Designation of Substituent Constants

O O Y electrophile Y H O H nucleophile pKA log KA H

KA
25 C Y

O O H O H H

KA

NO2 CN Cl H Me OMe

3.55 x 10-4 2.75 x 10-4 1.00 x 10-4 6.31 x 10-5 4.27 x 10-5 3.39 x 10-5

3.45

-3.45

0.75

3.56 4.00 4.20 4.37 4.47

-3.56 -4.00 -4.20 -4.37 -4.47

0.64 0.20 0.00 -0.17 -0.27

! = log (KY /K0 )

= log KY - log K0

KY : substituted acid K0 : unsubstituted acid

- Numbers tabulated for a variety of meta (!m ) and para (!p ) substituted benzoic acids - Positive ! values describe electron-withdrawing groups (weakens OH bond) - Negative ! values describe electron-donating groups (strengthens OH bond) Hammett, L . P. Chem. Rev. 1935, 17, 125.

The Hammett Equation

Key principle: All reactions that correlate to the Hammett equation will use the same set of substituent constants. That is, a structural modification will produce a proportional change in reaction rate based on the " values. Changes in structure produce proportional changes in !G . = !" This is necessary because -!G = RT ln k = 2.303RT log k Therefore, this is a LINEAR FREE ENERGY RELATIONSHIP.

Hammett Equation: log

kY k0

kY : rate of reaction for substituted benzene ring k0: rate of reaction for unsubstituted benzene ring
! : reaction constant ": substituent constant

Remember: ! G = ! H - T!S Since the relationship between free energy and !" is linear (for all reactions run at constant T), !H and ! S cannot be independent. (One consequence: ortho-substitution cannot obey the Hammett equation due to highly variable entropies from reaction to reaction.)

"
- Measurement of capacity to perturb electronic environment - First values described by Hammett - Referenced to hydrogen substituent (0.00) - Over the next 20 years, values averaged over several series of reactions to give good correlations for all

!
- Measurement of sensitivity of reaction to electronic perturbation - Individual for each reaction - Referenced to equilibrium of benzoic acids in water at 25 C (1.00) - Magnitude and sign can be diagnostic of reaction mechanism

A Simple Example: Basic Hydrolysis of Esters

O OEt Y OH , k Y
-

O O EtOH

Y NO 2 CN Cl H Me OMe

!
0.78 0.71 0.24 0.00 -0.14 -0.27

k (M-1 s-1 )
32.9 15.7 2.10 0.289 0.172 0.143

2.5

p-NO2

" = 2.54

p-CN

1.5

log

kY kH

p-Cl

0.5

p-OMe p-Me
-0.5 -0.4 -0.2 0

unsub

0.2

(! values readjusted to more recent average relative to benzoic acid equilibria)

0.4

0.6

0.8

Value of " (>1) tells that reaction is more susceptible to electronic perturbation Consistent with mechanism of hydroxide ion attack at carbonyl center

Hammett, L. P. Chem. Rev. 1935, 17, 125.

Some Basic Math

y = mx + b b: y-intercept
16

m: slope

Logarithm Rules: log (xy) = log x + log y log x y = log x - log y

14 12 10 8 6 4 2 0 0 1 2 3 4 5 6 7

y = 2x + 3 (m = 2, b = 3)

In the context of the Hammett Equation...

log

kY k0

": x-variable
= !" = log kY - log k0 log kY : y-variable log k0 : y-intercept Most people will plot " vs. log (kY /k0). Therefore, the y-intercept is meaningless, and only the slope of the line will give information.

log kY = !" + log k0

!: slope

What Contributes to !?
Resonance effects Inductive effects
Classical inductive effect (through-bond) "# "+ "# O ""+ Field effect (through-space) Through-bond evidence: OMe O cannot be stabilized by resonance n !m !p 0 1.04 0.88 (CH2)n NMe3 1 0.4 0.44 2 0.16 0.13 3 0.06 0.02 NMe3

MeO

O "#

MeO

Through-space evidence: Electron-withdrawing groups: +! Electron-donating groups: #! Me2 N (H2C)2 NMe2 (CH2)2 deuterates 105 slower than

Sign of " can be Diagnostic of Mechanism

O Yn OR H , H2 O Yn O OH ROH

O Ar O H

AA1 mechanism
O Electrons going toward aromatic ring Increased by EWG (+!) R = i-Pr 0 C in 98.7% H2SO 4 Ar O H

AAc mechanism
Electrons going away from aromatic ring Increased by EDG (-!) R = Me 65 C in 100% H2 SO4 with H[B(HSO4 )4 ]

-2

" = 1.99
-0.5

4-Cl,3-NO2 3-NO2 4-Me,3-NO2 4-NO2 3-Me,4-NO2

-2.2 -2.4 -2.6 -2.8

" = -0.825
4-NO2 3-NO2 4-Cl,3-NO2 3,4-NO2 3,5-NO2

-1

log k
-1.5

log k

-3 -3.2 -3.4

-2

4-Cl unsub

-3.6 -3.8 -4

-2.5 0 0.2 0.4

0.6

0.8

0.2

0.4

0.6

0.8

1.2

1.4

1.6

Hopkinson, A. C. J. Chem. Soc. B 1969, 203.

Magnitude of ! Value can be Important

5

! = 1.26 O OMe Y NaOH, H2 O 125 C Y log k125

3.5

O OH

4.5

p-NO2

p-Br

p-NH2

p-Me

unsub

2.5

2 -1 -0.5 0 0.5 1

Recall: O OEt Y OH Y O OH

"
Hypothesis: O O OH

! = 2.54 consistent with:

O OEt

Y Smaller ! value, therefore electronic effect is more removed from benzene ring.
18

O studies confirmed mechanism

Y OH

(Note ortho-substitution--ok for comparison purposes only!)

Goering, H. L.; Rubin, T.; Newman, M. S. J. Am. Chem. Soc. 1954, 76, 787.

Magnitude of ! can be Important (other cases)

O Yn OH

!
water, 25 C 1.00 1.52 O H3O 50% aq. EtOH

KA
H2O Yn

sensitive to rxn conditions (solvent, temperature, etc.)

Ionization of acids in water at 25 C: O Yn ! = 1.00 OH Yn O ! = 0.562 OH Yn ! = 0.212 O OH

O Yn OH ! = 0.466 (transmission thru "-system better) Yn

O OH ! = 0.256 (transmission thru 2 pathways better than 1)

Magnitude of ! can be Important (other cases-compensating effects)

O Yn NH2 H H2O Yn

O OH NH3 ! = 0.12

Pre-equlibrium protonation makes negative contribution to ! , but nucleophilic attack makes a positive contribution. Two effects cancel each other out.

Yn

Br OH Yn

OH Br ! = -0.33

Attack of hydroxide facilitated by EWG, but bromide leaving facilitated by EDG. Effects cancel, leaving a small reaction constant.

I Yn EtO Yn EtOH I ! = 2.07

Deprotonation assisted by EWG, but iodide leaving assisted by EDG. However, compensating effect of halide release is small due to more remote positioning.

Initial Hammett Values Inadequate for Some Reactions

Cl Yn H2O

90% aq. acetone 25 C Yn

OH HCl

via: Yn Correlations are not that good, especially with para substitution

meta-substitution
-3 -3.5 -4 -4.5 -5

para-substitution
0

t-Bu

Me unsub

OMe SMe Me

-1

SMe OMe

-2 -3

t-Bu
unsub

F Cl

log k

-5.5 -6 -6.5 -7 -7.5 -0.2 0 0.2

CO2Me Cl Br CF3 CN NO2

log k

-4 -5 -6

Br CO2Me CN CF3 NO2

0.8 1

-7 -8 -0.4

0.4

0.6

0.8

!
Stock, L. M.; Brown, H. C. Adv. Phys. Org. Chem. 1963, 1, 35.

-0.2

0.2

0.4

0.6

Brown Introduces !+
Cl Yn H2O 90% aq. acetone 25 C Yn OH

HCl

Brown's modification of the Hammett Equation: log

Applied to reactions where a cation or near-cation is developed Meta values relatively close to Hammett ! values

kY k0

= " +! +

Para values for EDG differ greatly from Hammett ! values due to resonance stabilization " + = -4.54
0

meta-substitution
-3 -3.5 -4 -4.5 -5

para-substitution
OMe SMe Me
-1 -2

Me

t-Bu unsub OMe

SMe

-3

t-Bu

log k

-5.5 -6 -6.5 -7 -7.5 -0.2

CO2Me F Br Cl CF

log k
CN NO2

-4 -5 -6 -7 -8

unsub Cl Br CO2Me CF3 CN NO2

0.2

0.4

0.6

0.8

-1

-0.5

0.5

!m +

!p +

Values are calculated from this reaction, but several reactions correlate well with these numbers. Brown, H. C.; Okamoto, Y. J. Am. Chem. Soc. 1957, 79, 1913. Stock, L. M.; Brown, H. C. Adv. Phys. Org. Chem. 1963, 1, 35.

!+ Applications
Benzylic alcohol oxidation: O Yn OH CAB, HClO 4 50% aq. AcOH 25 C correlation with !
0 -0.5

O S O Yn H Chloramine B (CAB) NHCl

0 -0.5 -1 -1.5 -2

correlation with !+ " + = -2.14

p-OMe

p-OMe

-1 -1.5 -2

log k

-2.5 -3 -3.5 -4 -4.5 -5 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

log k

-2.5 -3 -3.5 -4 -4.5 -5 -1 -0.5

!
Mechanism thus proposed involves cationic intermediate: OH Ar H H Cl NHSO2 Ph Ar slow

!+

0.5

OH Ar

OH H

Mukherjee, J.; Banerji, K. K. J. Chem. Soc., Perkin Trans. 2 1980, 676.

!+ Applications

H Yn

dimethylketene, AlCl3 Yn

O CHMe2 " + = -6.6

Dramatic effects and high correlations can be seen when reaction center is on ring.

Yn

HBR2 Yn

BR2

" + = -0.49

EDG will accelerate attack on boron, while EWG will facilitate hydride addition at the benzylic carbon. Effects will cancel each other out.

N Yn

N N3 Yn

N N

N3

" + = 3.7

Positive reaction constant due to cationic intermediate in the reactant rather than the product.

What About Anions?

Analogous modification of the Hammett Equation for anionic centers: kY = !- "log k0 NH2 H N Yn -H S O2
+

+ H+ NH2 N S O2

Values determined based on several reactions involving phenols and anilines (anionic in transition state). Correlation with "
-5 -5.5 -6 -6.5 -7

Yn

Correlation with "-5 -5.5 -6

log KNH

-7.5 -8 -8.5 -9 -9.5 -10 -0.4 -0.2 0 0.2

p-NO2 p-SO2NH2 p-CN p-COMe

-6.5 -7

log KNH

-7.5 -8 -8.5 -9 -9.5

0.4

0.6

0.8

-10 -0.5

0.5

1.5

"
+

"-

Values much closer to " values than " is to ". Only noticeable difference is in highly EWG in para positions. Yoshioka, M.; Hamamoto, K.; Kubota, T. Bull. Chem. Soc. Jpn. 1962, 35, 1723.

Reconciliation Between !, !+ , and !-: The Yukawa-Tsuno Equation

For all practical purposes, the three parameters (! , !+, and !-) are satisfactory for correlating reactions. Attempts have been made, however, to quantify the contributions between "normal" and "enhanced" resonance effects. The constant r expresses the degree of enhanced resonance Yukawa-Tsuno Equation log r = 0.00 for benzoic acid hydrolysis r = 1.00 for cumyl chloride hydrolysis (how !+ was defined) Analogous !- equation applied to anionic-type reactions
4 3

kY kH

= "(! + r(!+ # !))

O Yn H H2O r = 0.81: value indicates a largely-developed cation as the intermediate Yn

2 1

log krel

-1 -2 -3 -0.8

-0.6

-0.4

-0.2

0.2

0.4

0.6

! + 0.81(!+ # !) Yukawa, Y.; Tsuno, Y. Bull. Chem. Soc. Jpn. 1959, 32, 971.

Deviations from Hammett Correlations: Concave Up

Yn

Br N

acetone Yn

Br

Two possibilites:
0.25

1) Gradual change in transition state structure vs. Ar

0.2 0.15

Ar

Br

N log

0.1

kY k0

reagent-like ts

product-like ts

0.05 0 -0.05 -0.1

2) Complete change in mechanism (e.g. SN 1 to SN 2) py Ar Br Ar Ar py

-0.15 -0.2

0.2

0.4

0.6

0.8

!
Br Ar py Swain, C. G.; Langsdorf, W. P. J. Am. Chem. Soc. 1951, 73, 2813. Ar py solid circles: meta substituents hollow circles: para substituents Note: meta and para substituents should be divided in these situations due to their differing inductive and resonance contributions to reactivities.

10

Deviations from Hammett Correlations-Concave Down

Ph N Yn H HN

Ph OH2 NH2 O Yn Ph H

k1
Yn

k2

3.3

A concave down Hammett curve is indicative of a change in rate determining step.

3.2 3.1 3
unsub

m-OMe p-Cl m-Cl

Electron-rich groups will assist in step 1, making step 2 rate-limiting. Alternatively, electron-withdrawing groups will ultimately increase the rate of step 2, making step 1 rate-determining.

log kob s 2.9

2.8 2.7 2.6

p-Me

m-Me m-NO2

p-OMe

2.5 -0.4

-0.2

0.2

0.4

0.6

0.8

!
Hoffmann, J.; Klicnar, J.; Sterba, V.; Vecera, M. Coll. Czech. Chem. Commun. 1970, 35, 1387.

Deviations from Hammett Correlations-Concave Down

Y X

OH

k1 k-1

Y X

OH2

k2 k-2

Y X

k3
Y X Z visible by UV

Z visible by UV

X,Y,Z variously substituted--! and !+ values determined by simple summation of individual values Right side of plot: Ionization to carbocation is rate limiting. Not surprising, since EWG cannot stabilize this structure. Left side of plot: EDG can stabilize the carbocation through induction and/or resonance. Positive " + since the cation is the reactant (as in the aryldiazo-azide case)

1 0.5 0 -0.5

80% aq. AcOH w/ 4% H2SO 4 at 25 C

log kob s

-1

-1.5 -2 -2.5 -2

k3 : rds
-1.5

k2 : rds
-1 -0.5 0

!+

0.5

Hart, H.; Sedor, E. A. J. Am. Chem. Soc. 1967, 89, 2342.

11

New Models for Quantitative Analysis of Substitution Patterns

Relatively unused by experimental chemists--either poor correlations across reactions or too complex to be practical However, physical organic chemists sought to solidly divide substituents into separate resonance and inductive components The Taft-Ingold Equation: log

kY kMe
O

#": substiuent constant (almost of complete inductive nature) = !"#"( + !s E s )

Es : steric constant
O - Based on aliphatic systems - Resonance contribution essentially negligible

H2O OEt Y

EtOH OH

Wells, P. R.; Ehrenson, S.; Taft, R. W. Prog. Phys. Org. Chem. 1968, 6, 147. Roberts-Moreland work: Swain-Lupton extension: Defined R as the resonance substituent constant and fit several reactions to the equation: Measured acid dissociation constants of structures where resonance could not contribute: HOOC Defined an inductive substiuent constant: F Y Interestingly: #m = 0.57 F + 0.14 R #p = 0.49 F + 0.30 R Roberts, J. D.; Moreland, J. J. Am. Chem. Soc. 1953, 75, 2167. # = 0.34 F + 0.54 R #- = 0.46 F + 0.66 R
+

log

kY kMe

=f F + rR

Swain, C. G.; Lupton, E. C. J. Am. Chem. Soc. 1968, 90, 4328.

New Models for Quantitative Analysis of Substitution Patterns

The approach to developing modern "I and "R scales: Y N HOOC COOH O Y CH2 Y - Averaged to find "I OH H Y log Y COOH

KY KH

- All compounds should have minimal resonance contributions = !" I - Found ! for each ionization

Fit reactions to equation: log

"R

" R(BA)

"R+

"R P

kY kH

= #I "I + #R "R Y No direct resonance Y Weak interaction Y Strong acceptor Y Strong donor

with one of four types of " R where reaction occurs at center P

Note: even though this equation has two variable parameters, the correlation can be displayed in a linear graph via linear combinations. The dual-parameter approach has been moderately effective in correlations involving ortho substituents, and reactions through heterocyclic, olefinic, and aliphatic cores. Refs available in Isaacs, N. Physical Organic Chemistry ; Wiley: New York, 1995; pp 175-180.

12

Mechanistic Studies of Oxidative Addition

Previously reported:

Pd(PPh3 )4 H Me Br

Ph3 P Br Pd Ph3 P

H Me

Proceeds with 95% inversion

Lau, K. S. Y.; Wong, P. K.; Stille, J. K. J. Am. Chem. Soc. 1976, 98, 5832.

What about oxidative addition of C sp2 -X bonds with palladium catalysts?

R Path 1 RX Path 2 RX MI R , MIX "ionic" Not to be ignored... X M X M X M0 X R MII X "nonionic" M

Nucleophilic aromatic substitution considered an "ionic" pathway, like Path 2. At the very least, presence of charged intermediates separates it from the concerted mechanism. Amatore, C.; Pfluger, F. Organometallics 1990, 9, 2276.

Mechanistic Studies of Oxidative Addition

Consider the equilibria: (PPh3 )4 Pd (PPh3 )3 Pd (PPh3 )2 Pd ArI (PPh3 )3 Pd (PPh3 )2 Pd PPh3 PPh3 (PPh3 )2 Pd(Ar)I

K1 >> 1 (fast) K2 << 1 (slow)

Because K1 and K2 are equilbria between neutral species, they should be relatively independent of solvent polarity. As a consequence, any variation of activation parameters between solvents is directly attributable to the oxidative addition step.

Pd(PPh 3)4 and ArI in toluene, rt Variations of r between solvents would be indicative of changes in the activation parameters. (Remember LFER) " value for this reaction is nearly identical in THF. This indicates that solvation of charged intermediates is not involved in the oxidative addition step. It is most consistent, therefore, with a concerted, "nonionic" mechanism where charges are not developed (Path 1). Amatore, C.; Pfluger, F. Organometallics 1990, 9, 2276.
0.8

" = 2.3
0.6 0.4 0.2

p-Br p-Cl

log krel

unsub

-0.2 -0.4 -0.6 -0.3

p-Me

p-OMe
-0.2 -0.1 0 0.1 0.2 0.3

!
Compare with an electron transfer process: L nNi0 ArX

k
solvent

L nNiII (Ar)X

kTHF ktolu ene

= 8.8

Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 6319.

13

Attempts to Explain Better Heck Catalysts via Hammett Correlations

Heck reaction mechanism for oxidative addition to anionic palladium species: (o-tol)3 P (o-tol)3 P catalyst 1 + ArBr + OAc Pd - P(o-tol)3 (o-tol)3 P AcO reduction Pd + H+ eO Pd P O Ar2 O Pd O Ar2 P

catalyst 3

(o-tol)3 P AcO

Ar Pd Br

+ OAc

(o-tol)3 P Ar

Pd

Br Ar Pd Br P(o-tol)3

catalyst 2

Br CO 2 Bu R

2 mol % [Pd] NaOAc DMF, 130 C R

CO2 Bu

! - for cat. 1 = 1.01 ! - for cat. 2 = 1.00 ! for cat. 3 = 1.58

Hypothesis: Pd P Ar2 is the intermediate doing oxidative addition. The Pd-C bond is not broken.

Bohm, V. P. W.; Herrmann, W. A. Chem. Eur. J. 2001, 7, 4191.

An Atypical Ruthenium Oxidation Pathway Derived from Hammett Correlations

OH Xn Yn

O 2+ (TMC)Ru O CH3 CN, 40 C (BF 4 )2 Xn

O TMC: Yn ! = -1.44

N N

N N

1,4,8,11-tetramethyl1,4,8,11-tetraazacyclotetradecane

Did not correlate well with "+ values, unlike most other oxidations. Therefore, a more concerted process that doesn't invoke an # -carbocation is likely involved. Proposed rate-determining steps: O (TMC)Ru O or O 2+ (TMC)Ru O H HO CAr2 O (TMC)Ru O O (TMC)Ru OH Wang, Z.; Chandler, W. D.; Lee, D. G. Can. J. Chem. 1998, 76, 919. O CHAr2 O CHAr2 H 2+ OH + (TMC)Ru O OH CAr2 2+ H 2+ HO CAr2 [2+2] NOT: O OH (TMC)Ru OH CAr2 2+ O (TMC)Ru O H 2+ HO CAr2

14

Hammett Plots in the Oxidative Kinetic Resolution

O Yn OH 1.7 mol % (sparteine)PdCl 2 50 mol % sparteine Yn DCE, 1 atm O2 , 50 C (At high sparteine concentration, # -hydride elimination was found to be rate limiting.)
0.5 0.5

" = -1.41 0.15

0

" + = -1.00 0.13

0

p-OMe
unsub

p-OMe p-Me
unsub

-0.5

-0.5

p-Me

log kob s

-1

-1.5

m-OMe m-F

p-CF3 p-NO2

log kob s

-1

m-OMe
-1.5

p-CF3 m-F p-NO2

-2 -2.5 -0.4

-2 -2.5 -0.2 0 0.2

0.4

0.6

0.8

-1

-0.5

0.5

!+

"The calculated " and " + values...indicate that substituents influence the rate of both induction and resonance. The negative " value signifies a positive charge buildup in the transition state consistent with # -hydride elimination being rate limiting at high [sparteine]. The negative " + value specifies that direct resonance donation stabilizes the positive charge buildup at the benzylic center during rate-limiting #-hydride elimination at high [sparteine]."

Mueller, J. A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 7005.

Hammett Plots in the Oxidative Kinetic Resolution

Sigman's analysis is flawed! Hammett plots should be correlated to one set of parameters (i.e., ! or !+), not both sets. Both sets account inductive and resonance effects in varying degrees. In fact, a conclusion cannot be drawn based on this data, because only two substituents have notably different ! and !+ values. Substituent
0.5

" = -1.41 0.15

0

p-OMe
unsub

-0.5

p-Me

log kob s

-1

-1.5

m-OMe m-F

p-CF3 p-NO2

-2 -2.5 -0.4

-0.2

0.2

!
-0.27 -0.17 0 0.12 0.34 0.54 0.78

0.4

0.6

0.8

p -OMe p -Me
unsub

-0.78 -0.31 0 0.10 0.34 0.53 0.79

0.5

" + = -1.00 0.13

0

p-OMe p-Me
unsub

-0.5

m-OMe m-F p -CF3 p -NO2

log kob s

-1

m-OMe
-1.5

p-CF3 m-F p-NO2

-2 -2.5 -1 -0.5 0 0.5 1

!+
More data points, better accuracy, and perhaps a Yukawa-Tsuno analysis would be more appropriate.

15