Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups. Part 2 / 1215 1300

Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups.

Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd.

ISBN: 0-471-95171-4

CHAPTER 26

SN Ar reactions of amines in aprotic solvents

NORMA S. NUDELMAN

Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, 1428 Buenos Aires, Argentina

Fax: [phone]; e-mail: [e-mail]

I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		1216
II. SYSTEMS SHOWING CLASSICAL KINETICS . . . . . . . . . . . . . . . . .		1218
A. The Specific Base General Acid (SB GA) Mechanism . . . . . . . . . . .		1218
B. Medium Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		1220
1.	Mono-solvent parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1220
2.	Hydrogen-bonding scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1222
3.	Mixed solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1225
C. The Influence of the Nucleophile . . . . . . . . . . . . . . . . . . . . . . . . . .		1228
1.	Basicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1228
2.	Nucleophilicity and polarizability . . . . . . . . . . . . . . . . . . . . . . .	1232
3.	Steric effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1235
4.	Gas-phase basicity scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1237
5.	Solvation effects on relative basicities . . . . . . . . . . . . . . . . . . . .	1238
D. The Influence of the Substrate . . . . . . . . . . . . . . . . . . . . . . . . . . .		1240
1.	Steric and conformational effects . . . . . . . . . . . . . . . . . . . . . . . .	1240
2.	o- vs p-Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1241
3.	The field effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1243
4.	The nitro nucleofuge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1244
E. Molecular Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		1245
F. Electrophilic Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		1250
G. Aromatic Nucleophilic Substitution with Amines in which the
Nucleofuge is a Sulphur Derivative . . . . . . . . . . . . . . . . . . . . . . . .		1253
H. Aromatic Nucleophilic Substitution with Amines
under High Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		1256
III. SYSTEMS SHOWING ‘ANOMALOUS’ KINETICS . . . . . . . . . . . . . . .		1261
A. Fourth-order Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		1261
B. The Eight-membered Cyclic Transition state . . . . . . . . . . . . . . . . . .		1264
C. Aggregation of the Nucleophile . . . . . . . . . . . . . . . . . . . . . . . . . . .		1265
D. The ‘Dimer Nucleophile’ Mechanism . . . . . . . . . . . . . . . . . . . . . . .		1267

1215

1216			Norma S. Nudelman
E. Specific Solvent Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .				1272
F. Catalysis by Methanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .				1273
G. Catalysis by Hydrogen-bond Acceptor (HBA) Additives . . . . . . . . . .				1275
H. The Homoand Hetero-conjugate Mechanisms . . . . . . . . . . . . . . . .				1276
I. The Substrate			Catalyst Molecular Complex . . . . . . . . . . . . . . . . . .	1278
J. The ‘Desolvative Encounter Mechanism’ . . . . . . . . . . . . . . . . . . . .				1281
K. Conformational Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .				1282
L. Isotope Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .				1285
M. Further Treatment of Kinetic Results . . . . . . . . . . . . . . . . . . . . . . .				1286
1.	‘Inversion Plots’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .			1286
2.	Evaluation of the equilibrium constants . . . . . . . . . . . . . . . . . . .			1289
3. The dichotomy of amine effects in aromatic nucleophilic substitution
	(ANS) in aprotic solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . .			1290
IV. CONCLUDING REMARKS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .				1294
V. ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .				1294
VI. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .				1295
			I. INTRODUCTION
For neutral nucleophiles (e.g. amines, alcohols, water) there is much evidence				that

the addition elimination mechanism depicted in equation 1 fits very well most of the intermolecular and intramolecular nucleophilic displacements involving nitro-activated aromatic substrates1.

L	L	+ NuH	k3 B[B]	Nu
+ :NuH	k1	−		+ L− + H+
	k- 1
				(1)
EWG	EWG		k2	EWG

EWG = electron-withdrawing group	(1)

Some of the most important evidence for the two-step mechanism comes from studies of base catalysis, in this regard, reactions involving primary and secondary amines have played a central role1 5. The initially formed -adduct, 1, is zwitterionic and contains an acidic proton, which can be removed by a base which may be the nucleophile itself. Conversion of 1 to products can then occur via the uncatalysed k2 pathway or via the base-catalysed k3B pathway. The influence of Brønsted base catalysis, the experimental observation of 1,1- and 1,3- -adducts, the sensitivity of the system to medium effects, are some experimental evidence of the mechanism depicted in equation 1.

Assuming for simplicity that only a particular base B is an effective catalyst in equation 1, application of the steady-state approximation derives in equation 2 the expression of the second-order rate constant, kA, at a given concentration of B.

rate		k		k1k2 C k1k3B[B]	2
[Ar-L] [R1R2NH]	D		A D	k 1 C k2 C k3B[B]

Three main situations of interest with respect to the reaction shown in equation 1 were earlier considered in equation 22b.

(a) k2 C k3B[B] × k 1. In this case, no base catalysis is possible: equation 2 simplifies to kA D k1 and the formation of the intermediate is rate-limiting.

26. SNAr reactions of amines in aprotic solvents

1217

(b) k2 C k3B[B] − k 1. This situation corresponds to a rapid formation of the intermediate 1 followed by its rate-determining decomposition. In this case, equation 2 reduces to equation 3, which predicts base catalysis with a linear dependence of kA on [B]:

kA D	k1k2	C	k1k3B[B]	3
	k 1		k 1

(c) k2 C k3B[B] ³ k 1. In this intermediate situation, equation 2 indicates that base catalysis should be observed with a curvilinear dependence of kA on [B]. At low [B], the plot of kA vs [B] should be a straight line which will change to a plateau at high [B], where formation of the intermediate becomes rate-limiting. A downward curvature is expected on these grounds. Numerous kinetic studies devoted to the reactions shown in equation 1 have demonstrated the validity of equations 2 and 32 10.

The isolation and/or NMR spectroscopic characterization of -complexes, as that shown by 1, have received considerable attention over the past two decades, because of the relationship between the formation of such adducts and that of the metastable cyclohexadienyl intermediates postulated in the SNAr mechanism. The detailed structures of these adducts are now well known, and their reactions, the kinetics and thermodynamics of their formation and decomposition, as well as their spectral properties have been investigated in detail5,11,12. Although these studies constitute an important contribution to the understanding of the intermediates involved in SNAr, they will not be discussed in this chapter since they have been recently reviewed; furthermore, most of the -adducts were formed by the addition of anionic nucleophiles1a,5,11.

Many recent investigations have been also carried out in the field of heterocyclic compounds. As a result of the replacement of a ring carbon atom in an arene system by a more electronegative atom, the greater electron density on that atom and the concomitant reduction in electron density on the remaining carbon atoms make these substrates prone to suffer nucleophilic attack. A 1H and 13C NMR study of substituted nitropyridines and nitrobenzenes, and of their SNAr products obtained with amines, demonstrated that the electronic aza and nitro group effects are comparable if conjugation of the nitro group is not hindered12. Many SNAr reactions with nitro-activated heterocyclic compounds have been reported; however, a peculiar feature of aza-aromatic systems is that nucleophilic displacements of common leaving groups, as well as of hydrogen, can occur through multistep sequences involving ring opening reclosure (RORC) of the heterocyclic system13. These reactions are commonly referred to as SN(ANRORC) because they are promoted by initial addition of the nucleophile (AN) at an activated unsubstituted carbon1a,13. Evidence has been provided that this mechanism can operate to a large extent in the substitution of halonitropyridines by strong nucleophiles like OH in water/DMSO mixtures rich in DMSO, or with amide ions in ammonia14 16. The identification of the open intermediates16 constitutes a strong indication to suggest that the conversion of 2-halo-5-nitropyridines into the corresponding 2-hydroxypyridines occurs via the SN(ANRORC)-type process rather than via the anticipated SNAr mechanism. The feasibility of nucleophilic substitutions at the 4- or 7-position in condensed heterocycles such as nitrobenzofurazans has been also recently proved, and the finding of -adducts of the type found in trinitrobenzene analogues gives strong support to the operation of similar mechanisms17. Nevertheless, the observation of by-products indicates that nucleophilic attack also occurs at the annelated moiety with destruction of the heterocyclic system.

Numerous kinetic studies devoted to SNAr reactions with amines indicate that the occurrence and efficiency of base catalysis depend on the identity of the amine, the nucleofugue, the base and the solvent. In general, base catalysis is more often observed with secondary than with primary amines, with poor leaving groups and in the less polar solvents; one

1218	Norma S. Nudelman

of the three described kinetic situations is observed. Nevertheless, it will be shown in the forthcoming discussion that a new situation has been recently discovered: for several systems an upward curvature has been found in the plot of kA vs [B], which corresponds to a parabolic dependence of kA on [B], and a fourth-order kinetic law. Several alternative mechanisms have been proposed to account for this new kinetic finding.

Most of the more relevant findings related to SNAr reactions in the last decade have been observed in aprotic solvents, and the factors that have been studied with amines in aprotic solvents will be discussed. The first part will deal with works where some of the three kinetic situations described above have been found. In the second part, the systems where ‘anomalous’ kinetics have been observed will be discussed.

II.SYSTEMS SHOWING CLASSICAL KINETICS

A.The Specific Base General Acid (SB GA) Mechanism

For reactions in which the decomposition of the zwitterionic intermediate, ZH, is, at least partially, rate-limiting, two major mechanisms are now widely accepted. These are known as the specific base general acid (SB GA) and the rate-limiting proton transfer (RLPT) mechanisms and are shown in Scheme 11a.

In the rate-limiting proton transfer mechanism, the initially formed ZH undergoes ratelimiting, base-induced deprotonation followed by rapid uncatalysed or acid-catalysed leaving-group departure from the anionic intermediate, Z . This mechanism was initially proposed by Bunnett and Randall2d and then thoroughly studied by Bernasconi and coworkers3,18 who demonstrate that diffusion-controlled proton transfer steps can be overall rate-determining in multistep processes where the species undergoing deprotonation is present in a highly unfavourable equilibrium, or where reversion of this species is extremely rapid. This situation is clearly found for SNAr in protic solvents and this mechanism has been well established in those cases. On the contrary, for aprotic solvents the situation is still unclear.

The SB GA mechanism consists of a rapid equilibrium deprotonation of the ZH intermediate, followed by rate-limiting, general acid-catalysed leaving-group departure from the anionic -complex Z via the concerted transition state, 2. The derived expression for this mechanism is equation 4, where k4BH is the rate coefficient for acid-catalyzed

		!			Z	C
	expulsion of L from Z and K3 is the equilibrium constant for the reaction ZH
	BH.		k1k2 C k1k4BHK3[B]
	k				4
		A D k 1 C k2 C k4BH[B]

The SB GA mechanism was earlier established by Orvick and Bunnett19 for the reaction of 2,4-dinitro-1-naphthyl ethyl ether with n-butylamine and t-butylamine in DMSO, and it has been recently reported for the reactions of 2,4,6-trinitroanisole, 2,4,6- trinitrophenetole and methyl-4-methoxy-3,5-dinitrobenzoate with n-butylamine, and for the reactions of 2,4-dinitro-1-ethylnaphthyl ether with piperidine and pyrrolidine20 24. While the rate constants (k1 for formation of the zwitterionic intermediates) are consistent with the expected trend, i.e. pyrrolidine is more reactive than piperidine by a factor of 2.5, the results obtained for the decomposition of the intermediates were rather amazing. The rate constant k4 for the decomposition of the pyrrolidine adduct, Z , is about 11,000 times greater than that for the piperidine analogue20 24. Similarly, the general acid-catalysed decomposition of the pyrrolidine intermediate, ZH, is considerably faster than that of the piperidine analogue. Sekiguchi and coworkers21a have recently produced evidence that base catalysis in the substitution reaction of n-butylamine with

26. SNAr reactions of amines in aprotic solvents

1219

L

NO2

+ R1R2 NH

NO2

k −1 k1

L	+ NR1R2
	NO2	k3 B[B]

−k3 BH[BH]

NO2

ZH

k2

NR1R2

NO2

NO2

SCHEME 1

L NR1R2

NO2

−

NO2

Z −

k4 BH[BH]

+

B H L NR1R2

NO2

−

NO2

(2)

1-pyrrolidino-2,4-dinitronaphthalene also involves rate-limiting deprotonation of the zwitterionic intermediate.

All the available information indicates that the most plausible interpretation of these huge differences between systems apparently so similar, is in terms of stereoelectronic or conformational factors that result in destabilization of the transition states for general acid-catalysed expulsion of the leaving group in the piperidine system relative to pyrrolidine20,21. Interestingly, the sensitivity of the efficiency of the acid catalysis of the leaving-group departure to structural factors is in itself a criterion for the validity of the SB GA mechanism1. This mechanism has been also observed in other dipolar aprotic solvents like acetone or acetonitrile25,26; in the latter, catalysis by Cl has been observed26.

In non-polar aprotic solvents, however, the SB GA mechanism is more difficult to accept because of the known inability of these solvents to stabilize ionic species. The following discussion will consider the different proposals as well as several aspects that have been recently studied.

1220	Norma S. Nudelman

B. Medium Effects

Changes in reactivity due to transfer from protic to dipolar aprotic solvents were early recognized in SNAr reactions and some novel aspects have been recently studied11,27. Reactions carried out in the presence of crown ethers28,29, micellar surfactants and related modified micelles30 32, or under conditions of phase transfer cataysis (PTC)29,33 35, have been recently reported, as well as the effect of molten dodecyltributylphosphonium salts on SNAr reactions by halide ions36. Since most of these studies refer to anionic nucleophiles, they will not be discussed in this chapter.

1. Mono-solvent parameters

Many different approaches have been reported in the last decade toward a better understanding of the medium factors that influence reaction rates. Fundamental studies have been devoted to probe the reaction at a microscopic level in order to obtain information on the nature of several specific solvent solute interactions on SNAr and to attempt a description of these effects quantitatively. Recent works have shown the wide applicability of a single parameter scale such as the ET(30) Dimroth and Reichardt37, as well as other multi-parameter equations.

In this respect, the solvatochromic approach developed by Kamlet, Taft and coworkers38 which defines four parameters: Ł , ˛, ˇ and υ (with the addition of others when the need arose), to evaluate the different solvent effects, was highly successful in describing the solvent effects on the rates of reactions, as well as in NMR chemical shifts, IR, UV and fluorescence spectra, solvent water partition coefficients etc.38. In addition to the polarity/polarizability of the solvent, measured by the solvatochromic parameter Ł , the aptitude to donate a hydrogen atom to form a hydrogen bond, measured by ˛, or its tendency to provide a pair of electrons to such a bond, ˇ, and the cavity effect (or Hildebrand solubility parameter), υ, are integrated in a multi-parametric equation to rationalize the solvent effects.

The number of terms in the equation used to correlate the studied property (XYZ) depends on the significance of the solute solvent interactions. When the property studied refers to a single solute in multiple solvents, the general equation is usually expressed as equation 539:

XYZ D XYZ0 C s Ł C a˛ C bˇ C dυ 5

This solvatochromic solvent effect equation has been probably the most widely used one in the analysis of solvent effects40 and it has been applied to literally hundreds of processes in solution and for the correlation of all kinds of solvents effects39 43.

Application of these singleand multi-parameter analyses in SNAr will be referred to in many aspects discussed below. The importance of the hydrogen bond interactions has been also considered in other approaches which attempted to explain the solvent effects in these reactions43,44. Thus, two solvatochromic indicators for hydrogen bond donation and acceptance have been recently reintroduced, and the respective scales have been determined for 17 solvents45. H-bonding scales will be discussed in the next section. In some cases, the solvent hydrogen-bond basicity, ˇ, has been identified with the solvent nucleophilicity, but Bentley46 has recently pointed out that it is only an assumption. Nevertheless, there is a reasonable connection between the nucleophilic solvent parameter YC of Kevill and Anderson47 and the solvent ˇ values38a.

In SNAr involving amines as the nucleophiles, abundant recent studies afford evidence of the importance of the nature of the solvent in determining whether the formation or the decomposition of the zwitterionic intermediate will be the rate-determining step1,3b,20.

26. SNAr reactions of amines in aprotic solvents

1221

Furthermore, in many cases, changes in the mechanism have also been observed and they will be discussed in a later section. Nevertheless, by selecting a system that exhibited the same rate-determining step in a variety of solvents it would be possible to assess how the rate of a given process may be affected by a solvent transfer. Such is the case of the reaction of 1-chloro-2,4-dinitrobenzene with piperidine, where the rate dependence with amine concentration has been studied in 12 aprotic solvents48a as well as in 10 protic solvents48b. It was found that the reaction does not exhibit base catalysis in any of the solvents studied; that is, addition of piperidine is rate-limiting in all the cases48.

It is shown in Table 1 that for aprotic solvents, the rates increase with increasing solvent polarity, as a result of increased stabilization of the transition state leading to the zwitterionic intermediate. Many solvent parameters were tested and the best correlation was observed with the Dimroth Reichardt ET(30) values37. The observation of a satisfactory correlation between reactivity and the ET parameter in hydrogen bond acceptor aprotic solvents suggests that strong intramolecular hydrogen bonding between the ammonio proton and the ortho-nitro group is responsible for the stabilization of the ZH and of the corresponding transition state in these solvents48a. On the other hand, and in spite of increased polarity, the reactivity in hydroxylic solvents (Table 2) is slower than in any of the aprotic solvents studied and no correlation exists with ET values48b. In this instance, the reactivity is inversely proportional to the hydrogen bond donating ability of the solvent as measured by the ˛-hydrogen bond donor solvent parameter38. The fact that the rates are correlated by the hydrogen bond donicity of the hydroxylic solvent supports the view that the relatively low rates of substitution are the result of a strong solvation of the amine molecules48b. A similar effect will be also found in reactions discussed in Section III.

When the decomposition of the zwitterionic intermediate is rate-determining, the effect of the solvent is crucial since it may produce changes in the mechanisms and in the rate-determining step. A recent study of the kinetics of the reactions of 1-chloro-, 1- fluoroand 1-phenoxy-2,4-dinitrobenzene with piperidine, n-butylamine and benzylamine in ethyl acetate and THF indicated that these reactions resemble those in dipolar aprotic solvents when primary amines are the nucleophiles (i.e. that shown in equation 1, with

TABLE 1. Reaction of 1-fluoro-2,4-dinitrobenzene (DNFB) with							piperidine in aprotic solvents at
15 °C48a second-order overall rate coefficientsa
					103 [Piperidine] (M)
Solvent	ET(30)	0.625		1.25	2.50	5.00	7.50	10.0	12.5	15.0
Toluene	33.9				1.38	2.55	3.58	4.48	5.41	6.19
Benzene	34.5				2.34	3.70	5.09	6.45
Dioxane	36.0			2.06	2.57	3.42	4.11	5.05	5.83	6.67
Trichloroethane	36.2	2.48		3.28	5.35	8.48	11.7	15.0	17.5	20.7
Tetrahydrofuran	37.4	2.94		4.59	7.83	13.3	18.0	22.3	26.5	30.6
Chlorobenzene	37.5	4.23		5.22	8.42	13.7	18.4	22.4	24.7	28.0
Ethyl acetate	38.1	3.48		6.34	9.55	15.6	20.3	25.0	28.7	32.3
Chloroform	39.1			18.9	19.5	20.0	20.2	20.4	20.6
Dichloromethane	41.1				39.7	42.4	45.3	47.4
Acetone	42.2	24.8		31.6	44.3	64.9	79.5
Acetonitrile	46.0			87.9	99.4	110	114	116
Nitromethane	46.3			163	172	192

a [DNFB] D 5 ð 105M; kA in 1 mmol 1 s 1.

1222 Norma S. Nudelman

TABLE 2. Second-order reaction rate coefficients, kA, at 15, 25 and 40 °C, and activation parameters for the reactions 10 4 M of 1-chloro-2,4-dinitrobenzene with piperidine in hydroxylic solvents48b

		102kA (mol 1s 1)			H†	S†
Solvent		15 °C	25 °C	40 °C	(kJ mol 1)	(JK 1 mol 1)	ET(30)a	˛b	υSAc	ˇd
Methanol	0.801		1.41	2.80	39.0	151.7	55.5	0.98	3.0	0.62
Ethanol			1.80				51.9	0.83	2.1	0.77
2-Methylpropan-1-ol	1.05		1.90	4.61	41.9	145.3	49.0
Propan-1-ol	1.03		1.92	4.76	43.5	140.3	50.7	0.77	1.8
Propan-2-ol	1.40		2.51	6.25	42.7	141.1	48.6	0.70	1.5	0.92
Butan-2-ol	1.48		2.57	6.04	39.9	150.3	47.1
Benzyl alcohol	0.494		1.02	2.84	49.8	123.5	50.8	0.60		0.56
2-Phenoxyethanol	0.836		1.68	4.53	48.1	125.6	52.0
2-Methoxyethanol	2.34		4.01	9.09	38.4	151.6	52.3
Diethylene glycol	3.00		5.50	13.0	41.5	138.2	53.8

a Reference 37. b Reference 38a c Reference 38b d Reference 39

˛ D H-bond acidity; ˇ D H-bond basicity; υ D cavity effect.

a molecule of the solvent replacing that of base) and those in aprotic solvents when the nucleophile is a secondary amine.

SNAr reactions of nitroaromatics such as 1-chloro-2,4-dinitrobenzene and 2,4,6- trinitroanisole with amines are accelerated in micelles or microemulsions49. As with anionic nucleophiles, the rate enhancement is mainly the effect of a high local concentration of both reactants1a,31.

2. Hydrogen-bonding scales

One of the most comprehensive hydrogen-bonding scales is due to Abraham and his coworkers50, who have derived the general solvation equation 651

log SP D c C rR2 C s 2ŁH C a ˛2H C b ˇ2H C Vx

6

where SP is some solvent property of a series of solutes in a given system and the explanatory variables, or descriptors, are solute properties as follows: R2 is an excess

molar refraction, 2ŁH is the solute dipolarity/polarizability, and ˛2H and ˇ2H represent the solute overall hydrogen-bond acidity and basicity, respectively.

Thus, water octanol partition coefficients (log Poct) were shown to follow equation 7: log Poct D 0.088 C 0.562R2 1.054 2ŁH C 0.034 ˛2H 3.460 ˇ2H C 3.814Vx 7

Table 3 presents the parameters for an extensive set of solutes. The treatment has been successfully applied to the correlation of the reversed-phase HPLC capacity factors52,53. For a molecule with multiple hydrogen bonding sites, it has been found that additivity can be applied54 56. This additivity assumption has been successfully used in quantitative structure activity relationships (QSAR), in many reactions and particularly in drug design57 59. Some abnormalities observed by Abraham54 with pyridines and alkylpyridines in tetrachloromethane have been recently revisited, and the treatment has also been applied to other heterocycles employing 1,1,1-trichloroethane as solvent60.

26. SNAr reactions of amines in aprotic solvents

1223

TABLE 3. Solutes and their descriptors used in the regression equations72. Reprinted with permission from Reference 72. Copyright (1994) American Chemical Society

Solute	R2	2H	˛2H	ˇ2H	ˇ20	Vx
Benzene	0.610	0.52	0.00	0.14	0.14	0.7164
Toluene	0.601	0.52	0.00	0.14	0.14	0.8573
Ethylbenzene	0.613	0.51	0.00	0.15	0.15	0.9982
o-Xylene	0.663	0.56	0.00	0.16	0.16	0.9982
m-Xylene	0.623	0.52	0.00	0.16	0.16	0.9982
p-Xylene	0.613	0.52	0.00	0.16	0.16	0.9982
n-Propylbenzene	0.604	0.50	0.00	0.15	0.15	1.1391
Isopropylbenzene	0.602	0.49	0.00	0.16	0.16	1.1391
n-Butylbenzene	0.600	0.51	0.00	0.15	0.15	1.2800
Isobutylbenzene	0.580	0.47	0.00	0.15	0.15	1.2800
s-Butylbenzene	0.603	0.48	0.00	0.16	0.16	1.2800
t-Butylbenzene	0.619	0.49	0.00	0.16	0.16	1.2800
trans-ˇ-Methylstyrene	0.913	0.72	0.00	0.18	0.18	1.0961
Allylbenzene	0.717	0.60	0.00	0.22	0.22	1.0961
Biphenyl	1.360	0.99	0.00	0.22	0.22	1.3242
2-Methylbiphenyl	1.331	0.88	0.00	0.23	0.23	1.4650
3-Methylbiphenyl	1.371	0.95	0.00	0.23	0.23	1.4650
4-Methylbiphenyl	1.380	0.98	0.00	0.23	0.23	1.4650
Naphthalene	1.340	0.92	0.00	0.20	0.20	1.0854
Fluorobenzene	0.477	0.57	0.00	0.10	0.10	0.7341
Chlorobenzene	0.718	0.65	0.00	0.07	0.07	0.8388
2-Chlorotoluene	0.762	0.65	0.00	0.07	0.07	0.9797
3-Chlorotoluene	0.736	0.67	0.00	0.07	0.07	0.9797
4-Chlorotoluene	0.705	0.67	0.00	0.07	0.07	0.9797
Benzyl chloride	0.821	0.82	0.00	0.33	0.33	0.9797
2-Chloroethylbenzene	0.801	0.90	0.00	0.25	0.25	1.1206
1-Chloro-3-phenylpropane	0.794	0.90	0.00	0.24	0.24	1.2615
Bromobenzene	0.882	0.73	0.00	0.09	0.09	0.8914
2-Bromotoluene	0.923	0.72	0.00	0.09	0.09	1.0320
3-Bromotoluene	0.896	0.75	0.00	0.09	0.09	1.0320
4-Bromotoluene	0.879	0.74	0.00	0.09	0.09	1.0320
Benzyl bromide	1.014	0.98	0.00	0.20	0.20	1.0320
2-Bromo-1-phenylethane	0.974	0.94	0.00	0.30	0.30	1.1732
1-Bromo-3-phenylpropane	1.078	1.00	0.00	0.27	0.27	1.3030
Methyl phenyl ether	0.708	0.75	0.00	0.29	0.29	0.9160
2-Methylanisole	0.725	0.75	0.00	0.30	0.30	1.0569
3-Methylanisole	0.709	0.78	0.00	0.30	0.30	1.0569
Benzaldehyde	0.820	1.00	0.00	0.39	0.39	0.8730
2-Methylbenzaldehyde	0.870	0.96	0.00	0.40	0.40	1.0140
3-Methylbenzaldehyde	0.840	0.97	0.00	0.42	0.42	1.0140
4-Methylbenzaldehyde	0.862	1.00	0.00	0.42	0.42	1.0140
Acetophenone	0.818	1.01	0.00	0.48	0.48	1.0139
3-Methylacetophenone	0.806	1.00	0.00	0.49	0.49	1.1550
4-Methylacetophenone	0.842	1.00	0.00	0.51	0.51	1.1550
Ethylphenylketone	0.804	0.95	0.00	0.51	0.51	1.1550
n-Propyl phenyl ketone	0.797	0.95	0.00	0.50	0.50	1.2960
n-Butyl phenyl ketone	0.795	0.95	0.00	0.50	0.50	1.4370
n-Pentyl phenyl ketone	0.719	0.95	0.00	0.50	0.50	1.5780
n-Hexyl phenyl ketone	0.720	0.95	0.00	0.50	0.50	1.7190
Methyl benzoate	0.733	0.85	0.00	0.46	0.46	1.0726
Ethyl benzoate	0.689	0.85	0.00	0.46	0.46	1.2135

(continued overleaf )

1224	Norma S. Nudelman
TABLE 3. (continued)
Solute	R2	2H	˛2H	ˇ2H	ˇ20	Vx
Methyl 2-methylbenzoate	0.772	0.87	0.00	0.43	0.43	1.2135
Methyl 3-methylbenzoate	0.754	0.88	0.00	0.47	0.47	1.2135
Methyl 4-methylbenzoate	0.730	0.88	0.00	0.47	0.47	1.2135
Phenyl acetate	0.661	1.13	0.00	0.54	0.54	1.0730
Benzyl acetate	0.798	1.06	0.00	0.65	0.65	1.2135
Methyl phenylacetate	0.703	1.13	0.00	0.58	0.58	1.2135
Ethyl phenylacetate	0.660	1.01	0.00	0.57	0.57	1.3544
Methyl 3-phenylpropanoate	0.687	1.21	0.00	0.59	0.59	1.3544
Ethyl 3-phenylpropanoate	0.654	1.20	0.00	0.62	0.62	1.4953
Methyl 4-phenylbutanoate	0.693	1.29	0.00	0.59	0.59	1.4953
Dimethyl phthalate	0.780	1.41	0.00	0.88	0.88	1.4288
Benzonitrile	0.742	1.11	0.00	0.33	0.33	0.8711
2-Methylbenzonitrile	0.780	1.06	0.00	0.31	0.31	1.0120
3-Methylbenzonitrile	0.762	1.08	0.00	0.34	0.34	1.0120
4-Methylbenzonitrile	0.740	1.10	0.00	0.34	0.34	1.0120
Phenylacetonitrile	0.751	1.15	0.00	0.45	0.45	1.0120
3-Phenylpropanonitrile	0.771	1.35	0.00	0.51	0.51	1.1529
4-Phenylbutanonitrile	0.759	1.38	0.00	0.51	0.51	1.2938
Aniline	0.955	0.96	0.26	0.41	0.50	0.8162
o-Toludine	0.966	0.92	0.23	0.45	0.59	0.9570
m-Toludine	0.946	0.95	0.23	0.45	0.55	0.9570
p-Toludine	0.923	0.95	0.23	0.45	0.52	0.9570
2-Bromoaniline	1.070	0.98	0.31	0.31	0.39	0.9910
3-Bromoaniline	1.128	1.19	0.31	0.30	0.34	0.9910
2-Nitroaniline	1.180	1.37	0.30	0.36	0.36	0.9910
3-Nitroaniline	1.200	1.71	0.40	0.35	0.35	0.9910
4-Nitroaniline	1.220	1.91	0.42	0.38	0.38	0.9910
N-Ethylaniline	0.945	0.85	0.17	0.43	0.51	1.0980
Nitrobenzene	0.871	1.11	0.00	0.28	0.28	0.8910
2-Nitrotoluene	0.866	1.11	0.00	0.27	0.27	1.0320
3-Nitrotoluene	0.874	1.10	0.00	0.25	0.25	1.0320
4-Nitrotoluene	0.870	1.11	0.00	0.28	0.28	1.0320
Benzamide	0.990	1.50	0.49	0.67	0.67	0.9728
3-Methylbenzamide	0.990	1.50	0.49	0.63	0.63	1.1137
N-Methylbenzamide	0.950	1.44	0.35	0.73	0.73	1.1137
N,N-Dimethylbenzamide	0.950	1.40	0.00	0.98	0.98	1.2546
Phenylacetamide	0.950	1.60	0.52	0.79	0.79	1.1137
3-Phenylpropanamide	0.940	1.65	0.52	0.80	0.80	1.2546
Acetanilide	0.870	1.40	0.50	0.67	0.67	1.1133
Phenol	0.805	0.89	0.60	0.30	0.30	0.7751
o-Cresol	0.840	0.86	0.52	0.30	0.30	0.9160
m-Cresol	0.822	0.88	0.57	0.34	0.34	0.9160
p-Cresol	0.820	0.87	0.57	0.31	0.31	0.9160
2,4-Dimethylphenol	0.843	0.80	0.53	0.39	0.39	1.0569
2,5-Dimethylphenol	0.840	0.79	0.54	0.37	0.37	1.0569
4-t-Butylphenol	0.810	0.89	0.56	0.41	0.41	1.3387
2-Isopropyl-5-methylphenol	0.822	0.79	0.52	0.44	0.44	1.3387
2-Phenylphenol	1.550	1.40	0.56	0.49	0.49	1.3829
3-Phenylphenol	1.560	1.41	0.59	0.45	0.45	1.3829
4-Phenylphenol	1.560	1.41	0.59	0.45	0.45	1.3829
2-Chlorophenol	0.853	0.88	0.32	0.31	0.31	0.8975
3-Chlorophenol	0.909	1.06	0.69	0.15	0.15	0.8975
4-Chlorophenol	0.915	1.08	0.67	0.20	0.20	0.8975
2-Bromophenol	1.037	0.90	0.35	0.31	0.31	0.9501