Progress in physical organic chemistry volume 19

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 3 structural and medium effects on reactivity see Appendix I.. PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 9 bonding 32 Equat

PHYSICAL ORGANIC

CHEMISTRY VOLUME 19

ROBERT W TAFT, Department of Chemistry

University of Calqornia, lrvine, California

A Wiley-Interscience Publication

John Wiley & Sons, Inc

New York / Chichester / Brisbane / Toronto / Singapore

This text is printed on acid-free paper

An Interscience* Publication

Copyright 0 1993 by John Wiley & Sons, Inc

All rights reserved Published simultaneously in Canada

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1976 United States Copyright Act without the permission

of the copyright owner is unlawful Requests for

permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc

Libraty of Congress Cataloging in Publication m a :

Library of Congress Catalog Card Number: 63-19364 ISBN 0-471-52442-5

Printed in the United States of America

1 0 9 8 7 6 5 4 3 2 1

Universitat Autbnoma de Barcelona

Bellaterra (Catalonia), Spain

Institute of Organic Chemistry and Biochemistry

Czechoslovak Academy of Sciences

Prague, Czechoslovakia

Zdenkk Fried1

Institute of Organic Chemistry and Biochemistry

Czechoslovak Academy of Sciences

Prague, Czechoslovakia

V

vi CONTRIBUTORS TO VOLUME 19

Department of Chemistry

San Diego State University

San Diego, California

Universitat AutBnoma de Barcelona

Bellaterra (Catalonia), Spain

Tessek Laboratory

Institute of Analytical Chemistry

Czechoslovak Academy of Sciences

Brno Czechoslovakia

Introduction to the Series

Physical organic chemistry is a relatively modern field with deep roots

in chemistry The subject is concerned with investigations of organic chem- istry by quantitative and mathematical methods The wedding of physical and organic chemistry has provided a remarkable source of inspiration for both of these classical areas of chemical endeavor Further, the potential for

clearly anticipated The field provides the proving ground for the develop- ment of basic tools for investigations in the areas of molecular biology and biophysics The subject has an inherent association with phenomena in the condensed phase and thereby with the theories of this state of matter The chief directions of the field are: (a) the effects of structure and envi-

(c) applications of statistical and quantum mechanics to organic compounds and reactions Taken broadly, of course, much of chemistry lies within these confines The dominant theme that characterizes this field is the emphasis

on interpretation and understanding which permits the effective practice of

basic theories and methods of physical chemistry to the broad areas of knowledge of organic reactions and organic structural theory The nearly inexhaustible diversity of organic structures permits detailed and systematic investigations which have no peer The reactions of complex natural products have contributed to the development of theories ofphysical organic chemistry, and, in turn, these theories have ultimately provided great aid in the elucida-

Fundamental advances are offered by the knowledge of energy states and their electronic distributions in organic compounds and the relationship

of these reaction mechanisms The development, for example, of enen an empirical and approximate general scheme for the estimation of activation energies would indeed by most notable

physical theory well endows the field of physical organic chemistry with the frustrations of approximations The quantitative correlations employed in this field vary from purely empirical operational formulations to the approach

of applying physical principles to a workable model The most common

vii

INTRODUCTION TO THE SERIES

projected periodical series of volumes under this title will help serve this need The general organization and character of the scholarly presentations

Chemistry

We have encouraged the authors to review topics in a style that is not only somewhat more speculative in character but which is also more detailed

tative aspect of organic chemistry, authors have also been encouraged in the citation of numerical data I t is intended that these volumes will find wide use among graduate students as well as practicing organic chemists who are not necessarily expert in the field of these special topics Aside from these rather obvious considerations, the emphasis in each chapter is the personal

excellence of their individual presentations

volumes

By Keith Bowden and Edward J Grubbs

1

183

3lectronic Configuration, Structure, and Solvation of Phenyl-

By UlfEdlund and Erwin Buncel

rransmission of Substituent Effects: The Through-Space and

Through-Bond Models and Their Experimental Verification

By Otto Exner, Zdenik Friedl, and Tessek Laboratory

259

Linear Solvation Energy Relationships: An Improved Equation for

Solutes Including Polycyclic Aromatic Hydrocarbons and

One Century of Physical Organic Chemistry:

The Menshutkin Reaction

Madrid, Spain

Universitat Autdnoma de Barcelona

Bellaterra (Catalonia), Spain

C O N T E N T S

I Menshutkin and the Menshutkin Reaction 1

11 Thermodynamic Features of the Menshutkin Reaction 3

A The Database and Its Analysis 11

B The Role of the Nucleophile 13

1 Taft-Topsom Analyses 13

2 Br$nsted Analyses 22

3 Special Cases 27

C The Role of the Electrophile (RL) 28

1 Influence of the Substrate (R) 28

2 Influence of the Nucleofuge 38

1 Charge Separation within the TS 60

2 The Dissection of AV6 61

Progress in Physical Organic C h e m i s e , Volume 19

Edited by Robert W Taft Copyright 0 1993 by John Wiley & Sons, Inc

2 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

IV Quantum-Mechanical Approach 70

References and Notes 90

Appendix I Primary Sources of Kinetic Data 104

Appendix 11 Reviews on the Menshutkin Reaction 182

4 Isotope Effects and Mechanism 182

I MENSHUTKIN (1,2) AND THE MENSHUTKIN

REACTION

the chair of Analytical and Organic Chemistry at the then newly created Polytechnic Institute of Saint Petersburg In this respect, it is of interest that

his book Analytical Chemistry enjoyed a worldwide reputation

His paper “Uber die Affnitatkoeffzienten der Alkylhaloide und der

Amine” was published in 1890 (4) At that time, the quaternization of amines

constants of reactions taking place in solution are often solvent-dependent

rate constant for the quaternization of triethylamine with ethyl iodide

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 3

structural and medium effects on reactivity (see Appendix I) They are

“modern” in many respects, and most of his data are still valid Clearly, Nikolai Alexandrovich Menshutkin was “avant la lettre,” a quite brilliant physical organic chemist

The IUPAC defines (2) the Menshutkin reaction (MR) as the trialkyl-

ammonio-dehalogenation of alkyl halides:

Following the common practice we shall adopt here a somewhat broader

nitrogen bases in which the formal hybridization of the nitrogen atom is sp2

or sp3, with no restrictions imposed on the nature of the nucleofuge In

primarily on neutral electrophiles

thermodynamic and kinetic data available thus far A quantum-mechanical

MENSHUTKIN REACTION

All the experimental evidence seems to indicate that “gas-phase’’ MRs actually take place on the walls of the reaction vessel and/or on the solid salt (9) Quantitative studies on the systems Me,N(g)/MeI(g) (10) and Et,N(g)/

MeI(g) (1 1) show that actioation energies are negative and that the addition

of gaseous dipolar materials has little effect on reaction rates

In solution, the reversibility of MRs involving halides has long been

known (12)

Consider the reaction between a nitrogen base B and an alkylating

B + RL e BR+ + L - e BR+L- I BR’L- (3)

separate ions ion pairs solid salt

In the general case, products appear as separate ions, ion pairs (13), and solid salt

4 LL M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

The situation is greatly simplified by using highly dilute solutions of the reagents in solvents able to strongly solvate the ionic products:

kf

k

In this case, both k, and k, can be obtained directly (14) from separate

k , can be obtained by simultaneously monitoring the concentrations of

entails larger uncertainties (16)

The Lewis concept of acids and bases links proton exchange to exchanges

of other electron-accepting species (17):

B,H+ + B, e B, + B2Ht AAH;., K , , ( 5 )

B,BF3 + B, @ B, + B,BF3 AAHiF3, KBF3 (7)

The relationship between the MR and alkyl cation exchange between two

(4) for B, and B,:

Figure 1 shows that, for a given base, differential methyl cation affinities

(26), AAHLe+, are essentially independent of the solvent (27) (NB = C,H,N02;

data are as follows:

6 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

Various solvents 12.0

solvents versus the correspondent values in nitrobenzene solution

Differential methyl cation affinities for nitrogen bases (relative to pyridine) in various

changes for RCdction 6 in CH,CI, Reference base is pyridine

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REAGTION I

electron demand and, more likely, solvation

A wealth of kinetic data for forward and reverse alkylation reactions of

pyridines and other heterocycles is available (29), indicating that they should

ately, limited by the fact that they are obtained using very different temper- atures and solvents

Standard free-energy changes for the alkylation of N,N-dimethyl- anilines(30) [AGGA, Reaction lo] and pyridines (14) [AG;,, Reaction 111 with Me1 under formal conditions of equilibrium are presented in Table 2

This can be analyzed through the following cycle (32):

AC,., is the corresponding standard free- energy change for the transfer from

solvent S, into solvent S, Equation 12 follows:

In the absence of strong solvent-solute interactions (such as hydrogen

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 9

bonding) (32)

Equation 14 quantifies the differential effect of the solvent on the position

The availability of experimental standard enthalpies of formation for a variety of ions in the gas phase allows a comparison between solution and gas-phase reactivities

Let us consider Reaction 15 in the gas phase:

where AXT,,) is the change of the thermodynamic state function X for this reaction

Hence

Equations 15-18 show that the outcome of the MR Equation 15 is determined solely by the difference between the alkyl cation basicities of L- and B (33,34)

89kcalmol-'; AG:,,, is expected to be close to this value In MeCN, this

M R

The formation of solid salt is a strong driving force, of great importance

in poorly solvating media Both solvation and the formation of solid salt

10 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

tend to drive MRs to completion, but in the absence of surface effects or micellar catalysis (36), only the solvent is able to lower the activation barrier

of the elementary step:

Differential standard entropy changes for methyl cation exchange be- tween pyridines in MeCN, AASi,+(MeCN) are summarized in Table 3 Experimental uncertainties are large There is, however, a clear trend of

AAGi,+(MeCN) (see Table 3) From the fact that within families of bases,

effects and (b) solvent "freezing" is more important the less substituent-

stituent and solvent stabilization of organic ions has long been known (38)

To summarize:

to the thermodynamics of MRs in solution

2 McMahon and Kebarle (37a) and Mautner (37b) have given means of

proton affinities

Lewis (39), and their coworkers have provided a small set of reliable thermodynamic data for MRs and other alkyl transfers in solution

effects on the thermodynamics of alkyl-transfer reactions (39a) In this respect, quantum chemistry seems bound to play a key role

TABLE 3 DilTerential Standard Entropy and Free-Energy Changes, AAS&, (MeCN) and AAGie+ (MeCN),

for Reaction 1 1 in MeCN at 25.O"C (14)

"All values in cal mol- K ~ I

*Reference base: pyridine

'In kcalmole-

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 11

A The Database and Its Analysis

The truly impressive body of second-order rate constants k for Reaction

k

(“Products” can be either separate ions, ion pairs, or solid salt)

and the pressure (P) That is

Inspection of the original data shows that, under the same experimental

conditions (S,T,P), the mutual agreement between k values for a given

excellent (i.e., we11 within the limits of the combined experimental errors) to poor (differences of the order of magnitude of the constants) This is a con- sequence of uncertainties originating in the reversibility of the MR, ion-pairing, secondary reactions involving reactants and/or products (self-catalysis) and, likely, traces of impurities affecting conductimetric titrations

Frequently, uncertainties are largest for very reactive or very unreactive systems This is unfortunate, given the importance of these data for cor-

data sets for reactions involving a constant nucleophile (electrophile) and electrophiles (nucleophiles) having widely different structures, under condi-

Most of these studies are aimed at obtaining information on the structure

species (lifetimes of -0.1 ps), which until recently (40) have escaped experi-

experimental kinetic data are based on

1 The activated complex theory (41) Within its framework, the rate

formation of the activated complex (BRL) (standard free-energy of

12 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

activation for Reaction 20) are related through

("C = 1 moledm-3) The term I' is the ratio of the relevant activity

2 A principle of analogy, applying to

a Relationships between structural effects on the activation mag-

magnitudes for model reactions To this group belong the time-

honored Bry5nsted (43) and Hammett (44) analyses

transfer of TSs and model solutes (32,45)

The results from Brqhsted-Hammett treatments are generally discussed

rules, and (c) potential-energy surface plots (49) (PESPs)

All these methods fall short of providing a complete description of the TSs

The dissection of intrinsic (kinetic) and thermodynamic contributions

to AGI values has been carried out along the lines of Marcus theory (50) by

system (B,, R,L,) in a given solvent So Temperature and pressure are fixed

B, as well as R and R, are structurally related, it seems reasonable to link

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION \ 13 where X and Yare structural descriptors of B and R and AX and A Y measure

mutual influence of the structural change undergone by the reagents, (i.e.,

not been included in the actual analysis or have been found to be not statistically significant The importance of cross-terms for mechanistic studies has been emphasized by Dubois et al (55)

To our knowledge, an analysis along the lines of Equation 23 was first carried out on a MR by Kondo et al (56) These workers studied the “cross- terms” arising in the study of the quaternization of substituted N,N-dimethyl- anilines with 2,4,6-trinitroanisole in various solvents at 50.0”C

Expressions formally analogous to Equation 23 have been used by Claramunt et al (57), who approached the problem from a purely statistical

techniques and provides precise methodological guidelines

Bariou (58)

that, while limiting the number of experiments is important (even elegant), the “statistically prescribed minimal number of highly informative experi- ments” may not be sufficient from a chemical point of view This is so because large experimental errors might sometimes creep in the database and remain unnoticed in the absence of independent checks of the mathematical model

B The Role of the Nucleophile

The influence of steric effects on the kinetics of MRs being important (1 7, 29b, 59-67), we shall first consider the case of molecules in which these effects remain essentially constant

1

14 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

TABLE 4

Rate Constants k for Quaternization of 4-X-Substituted Quinuclidines with Me1 in MeOH"

X lo3 x k(lO.OC)b lo3 x k(25.O"Cr UF" U a + C

I 29 1.23 1.06

0.23

6.80 5.17 3.67 3.70 2.73 7.00

- 0.06 0.14 (0.19)' 0.12 (0.19)' 0.10 (0.19)' 0.30 0.24 (0.31)' 0.25 (0.28)' 0.45 0.45 0.44 0.60 0.65 0.19

- 0.42 -0.15 -0.17 -0.25 0.0 0.0 0.0

"All values in liters mol

*Values taken from Ref 69b

'Values from Ref 68

IEnhanced values of op suggested for the correlation of data In aqueous solution (Ref 71

'From Ref 71

and references cited therein)

These results show that

2 The quantitative ranking of substituent effects is solvent-dependent, as shown in Table 5

3 In both MeOH and MeCN, k values for alkyl derivatives increase

hydrophobic effects (70)

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 15

TABLE 5 Rate Constants for Quaternization of 4-X-Substituted Quinuclidines with Me1 in MeCN at 288 K

4 Taft and Topsom (71) have developed a formalism in which differ-

ential structural effects on the standard free-energy change for proton exchange

reactions (Equation 24), AACo,+, are treated as linear combinations of

polarizability (P), resonance (R), and field ( F ) effects, respectively quantified

These sets of parameters are appropriate for the study of acid-hse reactions,

both in the gas phase (71) and solution (23, 72) Notice that AAGH+ is a

measure of differential structural effects, as defined by Equation 24

for some reference compound; or (b) through transition-state theory, where

16 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

equation indicates that when rate constants change by a factor of 10, AAGI varies by some 1.3 kcalmol-' (at 298 K)

An analysis along these lines of data in Table 4 leads to Equation 27,

in which AAGi,, (MeOH) is referred to quinuclidine itself:

It is of interest that structural effects on the gas-phase basicity of 4-X-

substituted quinuclidines, AAG;, (g), are essentially determined by F, with

(69a,73), one finds again that AAGi+ (as) can be expressed as a linear

4-substituted pyridines (2) The most complete data set available is that for

the reaction of these compounds with EtI in C6H,N0, at 333K Rate constants for these reactions are presented in Table 6 Also, for comparison purposes, kinetic data on the alkylation of these compounds with Me1 in MeCN are given in Table 7

2

Table 8 summarizes the results of a Taft-Topsom analysis of AAGI and AAG;, values, pertaining respectively to the alkylation and protonation

of 4-X-substituted pyridines

instances, the values of p F and p R are quite "robust" (77) Values of p F and

of error The p F values are comparable to and slightly larger than the corre-

sponding value (2.92) for quinuclidines

With respect to AAG;, (g), both p F and p R are attenuated by an average factor of 0.1 5 (3.22/21.5; 3.30/25.9; 3.80/21.5; 3.61/25.9) close to the factor

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 17

TABLE 6 Rate Constants k for Quaternization of 3- and 4-X-Substituted Pyridines with EtI

different from the same ratio for AAGi+(aq) This implies that AAGi+(g) will

AHf Uncertainties on the activation entropies are important, but there is

activation become less negative, thus magnifying the energetic contribution to

18 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

TABLE 7 Activation Free Energies (AG:), Enthalpies (AH:), and Entropies (AS:) for Quaternization of

X-Substituted Pyridines with Me1 in MeCN (Reaction 11)

“In kcal mol- I

bValues calculated from the

‘In calmol-’K-’

(T = 298 K)

11.5 12.2 13.0 12.7 14.4 13.9 13.9 13.8 14.75

- 29.4 -31.8

- 30.8 -31.8

- 32.3

- 34.0 -32.1 -32.1

bExcluding the datum for X = 4-NH2

‘Number of data points

dSquare of the correlation coefficient

‘Standard deviation

’From Table 6

#From Table 7

hFrorn Ref 23

Work by Clarke and Rothwell (78) on the reactivity of 3,4- and 3 3 -

disubstituted pyridines shows that in the absence of significant mutual steric interactions, substituent effects are additive to a high degree of precision

ability under conditions of essentially constant field and resonance effects

PHYSICAL ORGANIC CHEMISTRY THE MENSHUTKIN REACTION 19

(71) Brown and Cahn (62b) indicate that these substituents exercise practi-

larger or smaller than 1.0 depending on the solvent The range of variation

is small, however Thus, polarizability contributions to AAG’ and AAHf

for the alkylation of 2 are small, and blurred by solvent effects

compounds (structure 4) this interaction disappears

are reported in Table 9

The results of a Taft-Topsom analysis of these data sets as well as of values of AAGi+(g) and AAGh+(aq) for 3 are summarized in Table 10 Conclusions drawn from these analyses are as follows:

At first glance this suggests that in the former series of reactions, the extent

of charge development on B is more important, thus implying a “later” TS

20 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

TABLE 9 Structural Effects on Differential Free Energies of Activation'**

for Alkylation of 4-X-Substituted N,N-Dimethylanilines with

Methyl Perchlorate (AAGiec,04y and Benzyl m-Nitrobenzene-

"Original data given in Table 9

'In kcal mol l

'Alkylation with methyl perchlorate

dAlkylation with benzyl m-nitrobenzene sulfonate

'Number of data points

'Square of the correlation coefficient

3 The comparison of p R for both alkylation reactions with those fo1

the attenuation factors are respectively 0.43 (6.21/12.7) and 0.88 (6.21/7.1:

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 21

0.49 (3.46/7.1) The attenuation of R effects is clearly much smaller than in the case of the pyridines At first sight, this is surprising, on account of the significant differences in the transmission of resonance effects

dines, substituent effects on AAGt are additive On the other hand, the alkyl-

with Me1 or alkyl bromide reveals that disubstitution leads to an enhancement

Taft-Topsom treatment are nicely rationalized by an extended Bransted treatment (see later)

In any case, all results agree with a model of the TS in which the nitrogen atom in B bears a positive charge:

MRs of ammonia and simple aliphatic amines (84)

Difficulties in handling some of these materials have been a powerful deterrent for most workers At this point, however, a fairly comprehensive database is already available Table 11 portrays representative results Within the family of the primary amines, rate constants steadily decrease with the length and branching of the alkyl substituents Using Menshutkin's

own data (they are good!) (84a, 84b), De Tar (67a) showed that rate constants

TABLE 1 1

Rates of Alkylation of Ammonia and Simple Alkylamines

RL=MeI; T=298 K; RL=MeI; S=C6H,; RL=C,H,COCH,Br;

0.0261' (303 K) 2.58'

1.09 (303K)'

-

-

3.22' 3.88' 1.10'

0.0190f0.0007 3.73 kO.10

"1n mol-' liters-1

bFrom Ref 84c

'Ref 84e

dRef 84g

22 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

can be correlated through

where E,(R) stands for Taft’s steric parameters (85)

k(R,NH) > k(R3N) In the case of tertiary amines, increases in the chain length beyond three carbons have little, if any, effect on the rate constants

Consideration of these facts along the lines of Fujita’s (86c) work suggests

that, in the absence of steric effects, the nucleophilicity of a series of amines

then assume that D(R) is a descriptor of the electronic effect of the alkyl

reaction rate in the absence of steric hindrance, an expression such as

is expected to apply (85)

reasonably expected to be a linear function of EJR) Then, for Equations 28a

kinetic data alone do not provide a means of determining khy9

Studies by Pankova and coworkers (87) on the reaction of alkyl-

in each of the series, reaction rates decrease according to H > M e > Et,

(c) MeOH levels these structural effects through hydrogen-bonding donation

nucleophilicity for a variety of bases having different structures requires the

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 23

comparison of the standard free-energy of activation AGiL(S) with the

this point, such an analysis can be carried out in only a few cases

Okamoto (89) has reported values of rate constants for the alkylation

of ammonia and the methylamines with Me1 in aqueous solution The fact that the sequence of nucleophilicities is the same in water and in benzene

to the products In particular, this suggests the absence of strong interactions between the N - H bonds of the activated complex and the solvent

This important conclusion has been systematically overlooked It is true, however, that approximate, family-dependent “extended Bransted” relation- ships between AGi,(S) and the aqueous pK, values of the bases have been

and quinuclidines

significant proton basicities (say, comparable to or higher than that of NH,) are linearly related with unit slope This opens up the possibility of generating

“extended Bransted” correlations through the comparison of AGi,(S) with ACi+(g) for the same bases Notice, also, that for pyridines, AACi+(g) and AAGie+ (MeCN) are linearly related, structural effects in solution being

As indicated by Salem (91) and discussed later on in this Chapter, the

TS of the MR results from a HOMO-LUMO (highest occupied-lowest

unoccupied molecular orbital) interaction involving the nitrogen lone-pair

We have shown recently (92) that for a variety of N(sp2) and N(sp3) bases,

high-quality linear relationships exist between the standard free-energy changes AGi+ (g) and AG;2 [solution(s)] pertaining respectively to gas-

molecular iodine in “inert” solvents;

All these results lead to a direct comparison of AAGi,(S) with AAGi+(g),

We have selected AAGLJMeCN) as there is good database for this property

24 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

is a flattened (93), relatively small methyl group so that front-strain effects

in s This correction actually transforms these differential gas-phase basicities

TABLE 12 Thermodynamic and Kinetic Data for Gas Phase Protonation and Alkylation of

Selected Bases with Me1 in MeCN at 298 K

- 18.5

- 29.0 -28.5 -4.5

'See Ref 84e

as indicated in the text

Oh

- 2.09' -3.31'

- 3.57' -3.88'

- 2.95k -4.69' 2.68"

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 25

unity and/or (b) in the case of bases having large aromatic frameworks, as

Figure 3 Differential structural effects on the free-energies of activation for the alkylation with Me1 of N(spz) and N(sp3) bases with Me1 in MeCN at 298 K versus differential gas-phase proton affinities for the same compounds (Data from Table 12)

26 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

The datum for N,N-dimethylcyclohexylamine is off the “sp3 line” by

compounds, thus corrected, are shown in Fig 3 This plot also shows that

as the electron-releasing ability of the substituents increases, there is a smooth evolution from a nearly “pure sp2” to a “mixed sp2-sp3” behavior This is obviously determined by an increasing pyramidalization of the basic nitrogen (104)

These results are the most comprehensive overall view of structural effects on MR nucleophilicity ever reported

The value AAGi,,(MeCN) decreases steadily (i.e., becomes more neg- ative) on going from NH, to quinuclidine This is associated to an increase

Thus, in the absence of significant front-strain, this desolvation is compensated

at least partially by polarization of the hydrocarbon framework of the base

is also the case for the activated complex in the MR This agrees with independent results by Kondo and coworkers (99)

Closer inspection of Fig 3 shows that NH,, MeNH,, and Me,NH define

an almost exact linear relationship of slope 0.200, while tertiary amines define

a line of slope 0.160 This might indicate a marginal contribution of steric effects in the case of the latter compounds

It is often considered (106) that the slopes of Bransted plots provide a measure of the extent of charge development on the nitrogen and/or of the

seems low If these hypotheses are accepted, and on account of the attenuation

to values estimated by Arnett

The pattern of reactivity of N,N-dimethylanilines is determined by

intriguing questions raised by the Taft-Topsom study of structural effects

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 27

on the reactivity of 3 are answered by Fig 3 Perhaps the conclusions of some important studies (82, 108) deserve a careful reassessment

5

bromide in EtOH at 35°C (109) are well described by a linear combination

These extended Br4nsted correlations pinpoint a number of bases for which more experimental data are needed: thus, we don’t know how AAHiJMeCN) and AASLJMeCN) vary with the structure of the base in

the case of many N(sp3) compounds In particular we ignore whether and

how steric differences (like those indicated above) are reflected by these magnitudes

3 Special Cases Many experimental results are not amenable to the same sort of studies because structural effects cannot be analyzed in terms of models such as the

Important examples involve work (1 10,ll la, 11 lb) on the alkylation of substituted thiazoles and polycyclic azaaromatics, respectively (see also

Consider the alkylation of two closely related bases B, and B, Supposing

that electronic effects are the same for both nucleophilic centers, the difference

and/or (Bl, B,)

This approach has been followed in studies of

1 Conformations of N, N-dimethylcyclohexylamines (100,112), N-alkyl-

2 The cis-trans interconversion of quinolizidine (6) and its methyl

6

28 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

3 The difference in reactivity of the exo- and endo-2-dimethylaminonor-

5 Stereochemistry of steroids (1 17) and alkaloids (1 18)

Perhaps one of the most challenging data sets yet to analyze is that of

C The Role of the Electrophile (RL)

reaction rates for the alkylation of MeNH, with alkyl iodides in MeCN at 25.0"C according to Matveev (84e) and Popov (84f)

Reaction rates are seen to be highly dependent on steric hindrance

Following Streitwieser (121), Niclas and Haussner (122) have defined a

1

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 29

TABLE 13 Structural Effects on Alkylation of Pyridine and Methylamine with Alkyl Halides

(0.781 +0.030) x

-

(6.01 k0.24) x (4.31 k0.16) x

This method has been used (122) for the analysis of rates of MRs

is, they combine both steric and electronic contributions (Representative values

For a discussion of the latter effect, Shaik's valence-bond configuration mixing (VBCM) theory provides a convenient conceptual framework This

method has been examined in detail in Volume 15 of this series (123) and is

TABLE 14 Structural Parameters ap and aap from Ref 122

- 1.26

- 3.63 1.67 2.27

~ 1.90

0

- 0.40

- 1.90 -0.53

- 1.40 -4.82 1.42 2.55

30 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

TABLE 15

Valence-Bond Description of Donor-Acceptor Configurations and Their Structural Effects on

the Transition State (124)

discussed in Section IV In this model, the general MR (Equation 34) is

considered as a single electron jump from B to L (Equation 35):

The two odd electrons are spin-paired and represent the new bond The wavefunction of the TS is then considered to be described by a linear combination of the wavefunction for configurations (BRL) (“no bonding”), (B+RL-) (“charge transfer”), and [B(RL)*] (“excited”), as summarized in

is still possible to extract information on electronic effects by comparing

Notice that, as oftoday, there is not a single set of data allowing a precise

This should be kept in mind in the following discussion:

a n-Electron Donor Substituents (0: < 0) Table 16 portrays data for reactions of quinuclidine with several compounds XCH,Cl in MeCN

A Taft-Topsom analysis of these values leads to

AAC’ = (3.07 f 0.02) + (13.72 f 0 0 3 ) ~ ~ + (43.88 f 0.10)0,+ (36)

In kcalmol-I, n = 4 , r2 >.999, sd=0.1 kcalmol-’

with the electrophilicity of ClCH,OCH, being comparable to and smaller than that of H,CSO,F (129,130) [Knier and Jencks (131) have given com-

*

PHYSICAL ORGANIC CHEMISTRY: THE MENSHUTKIN REACTION 3 1

TABLE 16 Differential Structural Effects on Standard Free Energies of

Activation for Alkylation of Quinuclidine with Compounds

@Defined through Equation 26

pelling evidence in favor of a ‘bona fide’ S,2 mechanism for many alkylation reactions (including MRs) involving chloromethyl methyl ether Its systematic

use [with appropriate precautions (132)] would be valuable]

Furthermore, p R is quite large, indicating that in the TS, the methylene group

their values for other systems (71) strongly suggests that it is important and

N(sp3) bases reacting with Me1 in MeCN

discussed by Kost and Aviram (1 33) These authors consider on the basis of

Figure 4

(a) X = halogen; (b) Molecular orbital interactions in the transition state X = OR (Taken from Ref 133.) of MRs involving X-CH,-CI:

32 J.-L M ABBOUD, R NOTARIO, J BERTRAN, AND M SOLA

lone-pair endowed with the largest p character takes an orientation minimiz- ing the overlap with the p orbital of the methylene group

The situation is exactly the opposite of that suggested by Equation 36 and by Jencks’ (1 31) work, which indicates a stabilizing interaction between

an empty orbital on the methylene and a filled orbital on X This is associated

to an enhanced stabilization of the “excited” configurations [B(RL)*] and a concomitant “loosening” of the TS In fact, the n-type orbital is neither completely “filled” nor completely “empty,” so that both stabilizing and de- stabilizing factors coexist

For X = SMe or SAr, Equation 36 predicts a substantial increase in

mental results on Finkelstein reactions (134a) as well as with Shaik’s (123) analysis of s N 2 reactions This author, however, predicts a rich, complex

that the TS is tighter than that for the reaction of CH3Cl It is obvious that these disagreements between leading workers in the field are disquieting and call for more experimental and theoretical work

modulated by varying the substituent X, under conditions of essentially constant steric hindrance:

9

4-methoxy- and 4-chloroaniline (Reactions 38 and 39)

AAG:38): substituent effects are far from being proportional