KINETICS AND MECHANISM OF HALOGEN DISPLACEMENT REACTIONS...

Chapter 1 Introduction

Ph D. Thesis K. B. Jose

Chapter 1

Introduction


Ph D. Thesis K. B. Jose - 2 -

1.1 Chemical Kinetics.

Chemical kinetics deals with the measurement of dynamic rates of chemical reactions

and the interpretation of experimental data to arrive at a possible mechanism [1].

Thermodynamics consider the initial and final states of a reaction and does not consider the

mechanism and the time required. The rate at which a reaction takes place need not be

directly related to the thermodynamic functions of the state of reactants and products.

Equilibrium can be treated in principle on the basis of kinetics considering it as a situation in

which the rates of the forward and reverse reactions are equal. The converse is not true; a

reaction rate cannot be understood on the basis of thermodynamics alone. Therefore,

chemical kinetics may be considered a more fundamental science than thermodynamics.

Unfortunately, the complexities are such that the theory of chemical kinetics is difficult to

apply with accuracy. As a result, we find that thermodynamics will tell with precision the

extent of a reaction, but only kinetics will tell the rate of the reaction.

1.1.1 Determination of rates of reactions

The rate of a given reaction can be determined by following the disappearance of a

reactant or the appearance of a product [1]. Any property that can be measured and

quantitatively related to the concentration of a reactant or product can be used to determine

the reaction rate. A complete kinetic investigation allows the reaction to be described by a

rate law, which is an algebraic expression containing rate constants as well as the

concentration of all reactants that are involved in the rate-determining step and steps prior to

the rate-determining step. The rate law must be established experimentally. In the rate law

each concentration term has an exponent, which is the order of the reaction with respect to

that component. The overall kinetic order of the reaction is the sum of all exponents in the



rate expression. Kinetics will invariably give a definite answer concerning the individual steps

of a chemical reaction.

The determination of reaction rate by conventional methods reduces to a study of

concentration as a function of time. The quantitative analytical procedures may be divided in

to two broad categories; chemical and physical. Chemical analysis implies a direct

determination of concentration of one of the reactants or products by volumetric procedures.

An important restriction on any chemical method is that it must be rapid compared with the

reaction being studied or if the method is relatively slow, the reaction must be stopped or

frozen by some sudden change such as lowering the temperature, removal of a catalyst,

addition of an inhibitor, or removal of a reactant. Chemical methods of analysis have the

advantage of giving an absolute value of the concentration. On the other hand, physical

methods of analysis are usually much more convenient than chemical methods. Physical

method is one which measures some physical property of the reaction mixture, which changes

as the reaction proceeds. There must be a substantial difference in the contribution of the

reactants and products to the physical property chosen. Common among physical methods are

measurement of pressure or volume change in gaseous reactions; optical methods such as

polarimetry, refractometry, colorimetry, and spectrophotometry; electrical methods such as

conductometry, potentiometry, polarography and mass spectrometry. Theoretically any

property which changes sufficiently could be used to follow the course of a reaction. In

general a physical method of analysis has the advantage of being rapid so that more

experimental points are available in a given time.



1.1.2 Isosbestic point

In spectroscopy, an isosbestic point is a specific wavelength at which two (or more)

chemical species have the same absorptivity. Such a point corresponds to a wavelength on an

isosbestic plot at which the absorption spectra of two species cross each other; if both species

are in the same concentration, then this represents the molar absorptivity (ε). This is

equivalent to saying an isosbestic point is a wavelength where two or more species have equal

extinction coefficients. A pair of substances can have several isosbestic points in their spectra.

When a 1-to-1(one mole of reactant gives one mole of product) chemical reaction involves a

pair of substances with an isosbestic point, the absorbance of the reaction mixture at this

wavelength remains invariant, regardless of the extent of reaction or position of equilibrium.

This occurs because two substances absorb light of that specific wavelength to the same

extent, and the analytical concentration remains constant. In chemical kinetics, isosbestic

points are used as reference points in the study of reaction rates, as the absorbance at those

wavelength remains constant throughout the whole reaction. Study of the progress of the

reaction using sequential scans with reaction mixture of known composition at different time

intervals gave progressive variation of absorbance with respect to time. The spectra thus

scanned gave important parameters like max value and also isosbestic points showing a neat

conversion of the reactant to product. [15].

1.1.3 Reaction mechanisms from kinetic data

In general the experimental results of studying the rate of a reaction as a function of

concentration, temperature, and other operating variables can be interpreted in several ways;

i.e., there are several conceivable mechanisms consistent with the data [1]. However, a

mechanism that is in agreement with the known facts may be discredited by data from new



experiments. The difficulty is due to the fact that all such postulated mechanisms are

essentially theories. The results of kinetic measurements furnish facts and mechanism is a

speculative model devised to explain the facts. In spite of this difficulty, many reactions

studied kinetically can be explained by a particular set of simple processes which are

reasonable and so in accord with all chemical experience that we accept them as essentially

true. The justification for this becomes apparent when it is observed that a mechanism can

successfully predict reaction products or the optimum conditions for running a chemical

reaction. The most important circumstantial evidence as to reaction mechanism is the

determination order of the reaction with respect to individual reactants hence overall order

and identity of the products formed. Nowadays molecular modeling by using ab initio

methods has been employed for making logical prediction of reaction mechanisms. The

comparison of the calculated activation energy with the experimental value and their

agreement between can be a support to the mechanism suggested on the basis of kinetic

investigations.

1.1.4 Reaction mechanisms from molecular modeling

Molecular modeling by using ab initio methods has been employed for making logical

prediction of reaction mechanisms. Molecular orbital calculations can be used for estimating

the energies of reactants, products and transition states which allow the determination of

activation energies [2]. Theoretical methods of investigation for postulating reaction

mechanisms, usually do not involve solvent effects but kinetic methods always include

solvent effects. For example, the mechanism of alkaline hydrolysis of amide has been

investigated by ab initio molecular orbital calculations using MP2 methods without

considering the solvent effects [3]. Another example is the study of substitution of 1-halo-



2,4-dinitrobenzenes by halide ions by applying density functional theory (DFT) in the B3LYP

model [4]. The SNAr mechanism of gas phase reactions of halo-nitrobenzenes with

carbanions has been investigated by DFT calculations to augment the experimental results [5].

1.2 Substitution Reactions of 1-substituted 2,4-dinitro aromatic compounds with amines.

Primary and secondary amines react with 1-substituted-2,4-dinitrobenzenes to form N-

substituted-2,4-dinitroanilines, Scheme 1, by nucleophilic displacement of the substituent [6,

36]. Compounds containing different substituents (e.g. halide, O-alkyl, O-aryl etc) at position

1 can be displaced with amines. The kinetics and mechanisms of these reactions have been

investigated in various conditions. Some of these reactions are strongly accelerated by bases,

but others are insensitive to base catalysis.

NO2O2N

Cl

+ NH2 R

NO2O2N

NH

R

Scheme 1

Nucleophilic substitution reactions of activated aromatic compounds with amines

usually involve the SNAr mechanism as shown in Scheme 2. When the second step is rate

limiting then general base catalysis may be observed. The investigations of the reactions of a

series of chlorodinitrobenzenes with primary and secondary aliphatic amines in acetonitrile

done by Crampton and coworkers [7] have established that the following factors affect the

values of k1 for nucleophilic attack: (a) Ring activation – values of k1 increase with increasing

electron withdrawal by ring substituents but ortho substituents, notably the CF3 group, can

have serious steric effects. (b) Steric effects at the reaction centre – values decrease with

steric congestion at the reaction centre. The steric effects due to leaving group increase in



order Cl < OPh and the steric effect of the nucleophiles increase in the order n-butylamine<

pyrrolidine ≈ piperidine. (c) Ground-state stabilization – involving resonance interactions

between the phenoxy group and the ring may decrease reactivity.

NO2O2N

X

NH

R

R

+k1

k-1 NO2O2N

NR2

N+ NO2

N+

X

H

R

R

O-

O-

k2

k3X = leaving group

(halide/OR)

Scheme 2

1.2.1 Displacement of chlorine/fluorine

The study of the kinetics and mechanisms of the displacement of chlorine from 1-

chloro-2,4-dinitrobenzene has been the subject of many investigations from 1950’s [8, 9] and

continues to attract the attention of many researchers. A recent example being the

investigation [10] of the effect of an ionic liquid, 1-ethyl-3-methylimidazoliumethylsulfate

([EMIM][EtSO4]) on the rate of the reaction between 1-chloro-2,4-dinitrobenzene and aniline

in methanol, chloroform, and dimethylsulfoxide containing at 25oC. Earlier, Nudelman and

coworkers [11, 12] described a kinetic and spectroscopic study of the reactions between 2,4-

dinitrochlorobenzene and aniline. The reactions were conducted in several benzene–n-hexane

mixtures at 40oC in the presence of variable amounts of aniline. Formation of various types

of electron donor–acceptor complexes and also of hydrogen bonded aggregates was clearly

recognized and the stability constants of several of those molecular complexes were

determined. The observed results afford evidence concerning the critical role that

complexation plays in the kinetic behaviour of these reactions. The reactions in aprotic

solvents exhibit a rate dependence that is third order in amine consistent with aggregates of



the aniline acting as the nucleophile [13, 14]. Molecular complexes between the aniline and

the substrate were also detected spectrophotometrically. Formation of N-(2,4-phenyl)aniline

was quantitative and pseudo first order kinetics were observed.

NO2O2N

Cl

+NO2O2N

NHNH2

Kinetic parameters have been reported for the reactions of 2-chloro-5-nitropyridine, 2-

chloro-3-nitropyridine, and the corresponding 2-phenoxy derivatives with n-butylamine,

pyrrolidine and piperidine and with n-butylamine and pyrrolidine in dimethyl sulfoxide

(DMSO) as solvent, Scheme 3, [15]. Kinetic measurements were made spectrophotometric-

ally at the absorption maxima of the products using Perkin-Elmer Lambda 2 or Shimadzu

UVPC spectrophotometers. Rate constants were determined at 25oC under first-order

conditions with substrate concentrations of 1×10−4

mol dm−3

and were evaluated by standard

methods. The kinetics of the same reactions in acetonitrile had been investigated earlier [16].

Values in these solvents are compared with those of 2,4-dinitrochlorobenzene, 2,6-

dinitrochlorobenzene, and the corresponding nitro-activated diphenyl ethers. Reactions with

n-butylamine in both solvents gave values of observed rate constants, which increase linearly

with amine concentration indicating that nucleophilic attack is rate limiting. The only

exception is the reactions in acetonitrile where base catalysis was observed.

N Cl

NO2

+ NH2 CH3

N

NO2

NH

CH3

Scheme 3



Bunnett and coworkers [17] have studied base catalysis of the reaction of N-

methylaniline with 2,4-dinitrofluorobenzene. They have shown that the reaction of N-

methylaniline with 2,4-dinitrofluorobenzene to give the substitution product, is sensitive to

base catalysis, whereas reactions with the corresponding chlorine and bromine compounds are

not. In ethanol, the catalyzed rate is linearly dependent on potassium acetate concentration. In

60% dioxane-40% water, the catalyzed rate shows less than linear response to hydroxide ion

concentration at higher concentrations of the base. The reaction is thus general base

catalyzed since acetate catalyzed reaction is not affected by the addition of acetic acid. These

observations are inconsistent with any form of one-step mechanism for the displacement

reaction. The kinetic data are, however, rationally interpretable in terms of the intermediate

complex mechanism shown in Scheme 4. In combination with other evidences previously

published, the present work firmly establishes the intermediate complex mechanism for a

large group of aromatic nucleophilic substitution reactions, and makes this mechanism

extremely probable for all such reactions.

NO2O2N

Cl

NH

Ph

CH3

+k1

k-1 NO2O2N

N

CH3

Ph

N+ NO2

N+

X

H

CH3

Ph

O-

O-

k2

k3

Scheme 4

The nucleophilic substitution reactions of n-butylamine (BU) and piperidine (PIP)

with 1-chloro-2, 4-dinitrobenzene and 4-chloro-3-nitrotrifluoromethylbenzene were studied

[18] in n-hexane, benzene and mesitylene. The reaction products were identified to be N-

(butyl)-2,4-dinitroaniline and N-2,4-dinitrophenylpiperidine, Scheme 5. The reactions seem



to follow a bimolecular SNAr mechanism for both substrates and amines. However, whereas

in n-hexane they are base catalysed, in the aromatic solvents only mild acceleration is

observed. The different behaviour of these reactions in the aromatic solvents in comparison

with hexane is explained by the specific solvent effect exerted by the aromatic compounds,

which solvates the aromatic reactant preferentially in view of its electron-donor properties.

These conclusions were confirmed by kinetic studies in hexane-aromatic solvent binary

mixtures. The presence of electron-donor solvents may inhibit SNAr reactions when

association constant of the solvent with the substrate is greater than the EDA constants

between the reactants. These specific solvent effects could also explain why only mild

acceleration is observed in aromatic solvents.

NO2O2N

Cl

NH2n-Bu+NO2O2N

NH

n-Bu

NO2O2N

Cl

+NO2O2N

NNH

Scheme 5

A kinetic and mechanistic study is reported [19] for nucleophilic substitution reactions

of 2,4-dinitro-1-fluorobenzene with a series of secondary amines, Scheme 6, in acetonitrile

and H2O at 25.0°C. The reaction in MeCN results in an upward curvature in the plot of kobs

vs. [amine], indicating that the reaction proceeds through a rate limiting proton transfer

(RLPT) mechanism. On the contrary, the corresponding plot for the reaction in H2O is linear,



implying that general base catalysis is absent. The ratios of the microscopic rate constants for

the reactions in MeCN are consistent with the proposed mechanism, e.g., the facts that k2/k-1 <

1 and k3/k2 > 102 suggest that formation of a Meisenheimer complex occurs before the rate-

limiting step and the deprotonation by a second amine molecule becomes dominant when

[amine] > 0.01 respectively. The Brønsted-type plots for k1k2/k-1 and k1k3/k-1 are linear with

ânucleophile values of 0.82 and 0.84, respectively, which supports the proposed mechanism. The

Brønsted-type plot for the reactions in H2O is also linear with ânucleophile 0.52 which has been

interpreted to indicate that the reaction proceeds through rate-limiting formation of a

Meisenheimer complex. DNFB is more reactive toward secondary amines in MeCN than in

H2O. The enhanced basicity of amines as well as the increased stability of the intermediate

whose charges are delocalized through resonance are responsible for the enhanced reactivity

in the aprotic solvent.

NO2O2N

F

+NO2O2N

N

Z

Z

NH

Z = CH2,

NH, N-CH2CH

2OH, NCHO and O

Scheme 6

The effect of the addition of small amounts of a protic ionic liquid, ethylammonium

nitrate, to a pure molecular solvent, such as acetonitrile changes the microscopic

characteristics of a reaction medium, was investigated [20]. Nucleophilic aromatic

substitution reactions between 1-fluoro-2,4-dinitrobenzene and n-butylamine or piperidine

was investigated to determine how the addition of known small amount of a protic ionic liquid



to a molecular solvent improve a reaction process. For the reaction with piperidine, a

decrease in the absorbance values of the substitution product corresponding to this amine

(λmax = 382 nm), can be observed at low concentrations of ethyl ammoniumnitrate (from 0 to

0.025 M). In contrast, the formation of a new species with λmax at 350nm was detected at

ethylamomonium nitrate concentrations greater than or equal to 0.05 M. The above result can

be understood by taking into account that EAN can act as a Bronsted acid and it can establish

acid–base equilibrium with amines, making possible to predict nucleophiles competition. For

the reaction with butylamine, the differences in the absorbance values with the increase of the

ethylammonium nitrate concentrations, cannot be observed because the wavelengths of

absorption for both products are similar. It was observed that the UV spectra for the products

from both amines at high EAN concentrations are coincident.

Akinyele and coworkers [21] have investigated the kinetics of the reactions of 1-

chloro-, 1-fluoro- and 1-phenoxy-2,4-dinitrobenzene, Scheme 7, with piperidine, n-

butylamine and benzylamine and in the case of the ether, morpholine were studied as

functions of nucleophile, DABCO and pyridine concentrations in tetrahydrofuran and ethyl

acetate. The reactions of the ether with n-butylamine and benzylamine in benzene were also

studied as functions of nucleophile, DABCO and pyridine concentrations. A comparison with

results in the literature indicated that the reactions in tetrahydrofuran and ethyl acetate

resemble those in dipolar aprotic solvents when primary amines are the nucleophiles and

those in aprotic solvents when the nucleophile is a secondary amine. An explanation is

suggested for the observation. While the reactions of 1-phenoxy-2,4-dinitrobenzene with

piperidine and morpholine in both tetrahydrofuran and ethyl acetate are strongly catalysed by



the nucleophiles, they are not catalysed by pyridine and there is either extremely weak or no

catalysis by DABCO.

NO2O2N

Cl

+NO2O2N

NNH

NO2O2N

O Ph

+NO2O2N

NNH

Scheme 7

Bunnett and co-workers [22] have claimed that the reaction of piperidine with 2,4-

dinitrochlorobenzene in 95% ethanol is first-order and not higher order in piperidine and that

added sodium hydroxide does not accelerate this same reaction in 50% dioxane-50%water.

Kinetics of reactions of aniline and n-butylamine with 2,4-dinitrofluorobenzene was studied.

It was argued that the observations exclude the possibility of base-catalysis in this and similar

systems.

Ross and coworkers [23] have measured the rates of reaction of 2,4-

dinitrochlorobenzene with n-butylamine and sodium hydroxide, both separately and together,

in a mixture of 50% dioxane-50% water at 24.8 ≠ 0.1o. The results suggest but do not prove

that the reaction with the amine is subject to catalysis by both n-butylamine and hydroxide

ion. Results have shown that a complete description of the reaction of 2,4-

dinitrochlorobenzene with both primary and secondary amines in chloroform and in ethanol

requires two kinetic terms, one first-order in amine and the other second-order in amine. In a

more detailed study of the reaction of 2,4-dinitrochlorobenzene with n-butylamine in



chloroform it was further found that added triethylamine, which does not itself react with 2,4-

dinitrochlorobenzene at an appreciable rate, nevertheless accelerates the rate of the reaction of

the chloride with n-butylamine.

Forlani and coworkers [24] studied the reaction between 1-fluoro-2,4-dinitrobenzene

and n-butylamine, Scheme 8, in toluene shows a two-step plot of observed rate constant

values vs. the initial values of the concentration of the amine. The usual base-catalysis

mechanism for HF elimination from the zwitterionic intermediate hardly explains this kinetic

behaviour and the kinetic effect of addition of salts (and of 2-hydroxypyridine) to the reaction

mixtures at different initial values of the concentration of n-butylamine. In contrast, the

kinetic behaviours are easily explained by the presence of substrate-amine (or catalyst)

interactions on the pathway of the substitution reaction.

NO2O2N

F

+NO2O2N

NH CH3

CH3NH2

Scheme 8

Mancini and coworkers [25] studied the kinetics of the reaction between 1-fluoro-2,6-

dinitrobenzene and pyrrolidine or piperidine, Scheme 9, in ethyl acetate–chloroform or

acetonitrile and acetonitrile–chloroform binary solvent mixtures. The kinetic response of these

reactions was compared with that of the reactions with piperidine. The aim of this work was

to evaluate the influence of the nucleophile structure and of solvent effects on those reactive

systems. The amine structure has a great influence on second-order rate constants, especially

on the rate constants related to the catalyzed step. In mixtures with chloroform the amine

structure is also responsible for the change in the reaction mechanism. Theoretical quantum



mechanical calculations confirm that the origin of these results lies in stereoelectronic effects

due to the conformational difference between the amino moieties in the intermediate adducts

as they release the leaving group. Solvation effects are dominated by non-specific

interactions.

NO2

F

NO2

+NO2

N

NO2

NH

Scheme 9

1.2.2 Displacement of OR/ OPh group

Most reactions of 2,4-dinitrohalobenzenes with amines are mildly accelerated by

bases, but the reaction of 2,4-dinitrophenyl ether with piperidine in 60% dioxane-40% water

is strongly base catalyzed [26, 27]. Crampton and coworkers [28] found that in the reaction

of aniline with 2,4-dinitrophenyl 2,4,6-trinitrophenyl ether in acetonitrile conversion of the

zwitterionic intermediate to products was rate determining and involved both uncatalysed, k2,

and base catalysed, kB[B], pathways. Further, they have reported [29] a kinetic study of the

reactions of anilines containing both remote- and ortho-ring substituents, allowing the

electronic and steric effects on the individual steps in Scheme 10. The kinetic data show that

increasing substitution does not sterically inhibit nucleophilic attack by aniline. The results

show that although substituents at the 3- or 4-positions of the anilines have only small steric

effects, alkyl substituents at the 2-position may result in considerable reductions in reactivity.

In general, the reactions are base catalysed so that a rate-limiting deprotonation of the

zwitterionic intermediate occurs. Only with the dinitro derivatives an uncatalysed reaction



involving intramolecular proton transfer is observed and for 2,6-dinitro derivative this

pathway takes all the reaction flux. These effects are more pronounced for the base-catalysed

pathway and in 2,6-dimethylaniline the uncatalysed pathway takes all the reaction flux. In the

case of the 2-fluoro substituent the electronic effect, strong inductive electron withdrawal, is

dominant over steric effects.

X

EWG

+ NH

R

R1

X N+

R

R1

H

EWG

-

k1

k2

NR R

1

EWG

k2

kB

+ HX

EWG = Electron withdrawing group

Scheme 10

Crampton and coworkers [30] presented a detailed and comprehensive analysis of the

competitive behavior of σ-adduct formation versus nucleophilic substitution in the reactions

of the three aliphatic amines with 2-ethoxy- and 2-phenoxy-3,5-dinitropyridine in DMSO.

Most results refer to DMSO but comparison is made with results in acetonitrile and in

dimethylformamide. As with methoxide, initial attack is at the 6-position, however, the use of

amine nucleophiles allows the slower attack at the 2-position, leading to irreversible

substitution, Scheme 11. The ratio of the rate constants for attack by n-butylamine at the

unsubstituted 6-position (k6) and 2-postion (k2) is 2000 for 2-phenoxy-3,5-dintropyridine and

8000 for 2-ethoxy-3,5-dintropyridine. This contrasts with the behavior of 1-ethoxy-2,4,6-

trinitrobenzene, where there are considerable sterric interactions around that position [31].

Here, the ratio of the rate constants, k3/k1, for attack by n-butylamine at the unsubstituted 3-

position and the 1-position, is only 13.



N

O

NO2

O2N

CH3

+NH

N

NO2

O2N

N

N

O

NO2

O2N

Ph

+NH

N

NO2

O2N

N

Scheme 11

The reactions of 2,6-dinitrophenyl phenyl ether and of 6-methyl-2,4-dinitrophenyl

phenyl ether with piperidine, morpholine, butylamine and benzylamine are base catalysed in

both dimethyl sulfoxide and acetonitrile [32]. The reaction of 2-phenoxy-3,5-dinitropyridine

with aniline is base catalysed in acetonitrile, but not in dimethyl sulfoxide, and its reactions

with piperidine, morpholine, butylamine and benzylamine in acetonitrile are also base

catalysed. The results are discussed in terms of the prevailing theories of aromatic

nucleophilic substitution reactions. Increase in activation of the substrate increases the k2/k-1,

and k3/k-1, ratios. For ortho substituents, steric/steroelectronic effects in the transition state

reduce both k-1, the rate constant for the decomposition of the zwitterionic intermediate to

reactants, and k2 and k3, the rate constants for its decomposition to products. When the

substrate has two ortho nitro groups the primary and secondary amines show different

behaviour but the same is not found when the substrates contain only one ortho-nitro group.

Chamberlin and coworkers [33] have investigated the reactions of morpholine in

dimethyl sulphoxide at unsubstituted ring positions of 1,3,5-trinitrobenzene, and phenyl 2,4,6-

trinitrophenyl ether, yield anionic σ-adducts via zwitterionic intermediates. Reactions at the 1-



position of phenyl 2,4,6-trinitrophenyl ether, phenyl 2,4-dinitronaphthyl ether, and phenyl

2,4-dinitrophenyl ether result in substitution of the phenoxy groups. In both types of reactions

the rate-determining step is a proton-transfer. Comparison of kinetic and equilibrium data

with those for corresponding reactions of piperidine shows that rate constants for proton

transfer are similar for the two amines, but equilibrium constants for zwitterion formation

have lower values for morpholine, the less basic amine. Implications for base catalysis are

discussed.

Banjoko and coworkers [34] studied the kinetics of the reactions of phenyl 2,4,6-

trinitrophenyl ether with piperidine and cyclohexylamine respectively at different amine

concentrations in benzene. The reaction of cyclohexylamine was not base-catalysed while that

of piperidine was catalysed by one molecule of the nucleophilic amine. Addition of small

amounts of hydrogen-bond donor solvent, methanol to the benzene medium of the reactions

produced different effects-rate diminution followed by rate increase in one and continuous

rate diminution in the other. These effects are compared with that of aniline in which a

continuous rate increase was observed. The results are rationalized in terms of the effect of

amine-solvent interaction on the nucleophilicity of the amines in addition to some other

factors operating through cyclic transition states leading to products. It is evident from the

rationalization that the idea of ‘dimer nucleophile’ in nucleophilic aromatic substitution

reactions is erroneous.

1.3.1 Proposed mechanisms for SNAr reactions of amines

Based on the kinetic data mechanisms have been proposed for nucleophilic aromatic

substitution reactions of amines with 1-substituted-2,4-dinitrobenzene. In general, the SNAr

reactions proceed via mechanisms involving a first step in which attack of a nucleophile on an



electron-deficient aromatic halide gives an anionic ó-bonded adduct, commonly termed a

Meisenheimer complex (MC) [7,19]. When the nucleophile is a primary or secondary amine

and the leaving group is a halide ion, the first-step in the SNAr process (Scheme 1) probably

leads to formation of a zwitterionic Meisenheimer complex from which two competitive

processes for decomposition have been postulated: (1) expulsion of the fluoride ion leaving

group followed by rapid proton loss from the protonated product dinitroaniline to give the

new substituted aniline (2) base-catalyzed deprotonation of the Meisenheimer complex to

yield a new amino-Meisenheimer complex, an anion that loses fluoride ion to give the same

new aniline product, Scheme 12. Similar mechanism has been proposed for the displacement

of chlorine from 1-chloro-2,4-dinitrobenzene using primary and secondary amines. Results

from kinetic studies indicate that the rate determining step is the formation of the

Meisenheimer complex both in polar and non-polar solvents when the leaving group is a

halide ion.

NO2

O2N

F NH

R

R1

NO2

O2N

F

N+

R

R1H

NH

R

R1

NO2

O2N

F

N

R

R1

NO2

O2N

N

R

R1

- F-

- H+

- F-

NO2

O2N

N+

R

R1

H

NH

R

R1

- H+

MC Anion



Scheme 12

However, the displacement of an OR or OPh group by primary or secondary amines

proceeds via Meisenheimer complexes but the rate determining step is the decomposition of

the complex, i.e. the deprotonation of the zwitterionic intermediate to form an anionic

intermediate which dissociates to yield the products as indicated by kinetic measurements

[35]. It was shown that the reaction is first order with respect to the substrate and second

order with respect to the amine and overall reaction is third order [6,36].

NO2

O2N

OPh

NH

R

R1

NO2

O2N

OPh

N+

R

R1H

NH

R

R1

NO2

O2N

OPh

N

R

R1

NO2

O2N

N

R

R1

- PhOH

- H+

MC Anion

Scheme 13

1.3.2 Molecular modeling of mechanisms for SNAr reactions

Aromatic nucleophilic substitution reactions are an important class of organic

reactions having synthetic applications and continue to inspire studies related to its kinetics

and mechanisms [35]. Studies have revealed that the displacement of the substituent at 1-

position is faster when the aromatic ring contains electron-withdrawing substituents at ortho



and para positions [7]. Mechanisms involving the formation and decomposition of

Meisenheimer complexes have been proposed for SNAr reactions on the basis of kinetic

studies [6]. The effect of electron-withdrawing substituents and solvents on the rate of the

displacement of fluorine, chlorine or phenoxy group at position-1 by primary and secondary

amines has been the subject of many investigations [6, 7, 10, 11, 35]. Most of the reports on

kinetic measurements agree that the reaction is second order, first order with respect to the

substrate and first order with respect to the amine, and the rate determining step is the

formation of the Meisenheimer complex. The mechanisms proposed on the basis of

experiments involving the measurement of order of reactions, solvent effects and base

catalysis have been summarized recently [16, 37].

Molecular orbital calculations using Density Functional Theory (DFT) is being

increasingly used for deducing and understanding organic reaction mechanisms in the

molecular level. DFT calculations have been extensively used for elucidating gas-phase

reactions studied using mass spectrometry [38, 39, 40, 41]. The mechanisms of few aromatic

nucleophilic substitution reactions have been investigated by performing theoretical

calculations. For example, the mechanism of nucleophilic displacement of chlorine from 1-

chloro-2,4-dinitrobenzene by thiomethoxide ion (CH3-S-) was recently investigated by both

Hartree-Fock and MP2 methods and the geometries of the intermediates and transition states

were optimized using 6-31+G** basis set [42]. The mechanism involves the formation of

Meisenheimer complex between thiomethoxide ion and 1-chloro-2,4-dinitrobenzene. The rate

determining step is the formation of the Meisenheimer complex and the estimated energy

barrier for its decomposition to products is very small. The calculations also demonstrate that

the barrier for formation of the Meisenheimer complex is higher than the breakdown of the



Meisenheimer complex, which is in agreement with previous experimental observations in

solution. The free energy profile for this reaction in aqueous solution has also been calculated

at the HF/6-31+G** and MP/6-31+G** levels of theory and showed that hydration affects the

aromatic nucleophilic substitution. The results of this study has been utilized for the

theoretical modeling of the enzyme catalyzed displacement of chloride ion by DFT

(B3LYP/6-311+G**) and PM3 methods [43]. Ab initio computational studies were carried

out on single-step and multistep mechanisms of aromatic substitution of halobenzenes and

halonitrobenzenes with halide anions with the GUASSIAN-92/DFT and GUASSIAN-94

systems [44]. The C6H5X + X- (X = Cl-I) gas phase SNAr reactions proceed via a single-step

mechanism without the formation of a stable C6H5X2- σ-complex. The C6H5F + F

- SNAr

reaction proceeds via a multistep mechanism with the formation of a discrete C6H5F2- σ -

complex as an intermediate, the energy of which is 15.5 kJ mol-1

lower than that of the

separated reactants. Another example explored DFT is the nucleophilic displacement of

fluorine by ammonia [45]. Nucleophilic aromatic substitutions of polyfluoroaromatic

compounds have been proposed to proceed by an addition-elimination mechanism (SNAr) via

an intermediate Meisenheimer complex, where a first transition state (TS1) is assumed to, in

general, determine the reaction rate, rather than a second transition state (TS2) involving a

C_F bond breaking. Calculations at B3LYP/6-31G* level of theory has been utilized to

estimate the energy profile of the reaction between ammonia and polyfluorobenzene and to

arrive at the relative energies of the transition states for the formation and decomposition of

the Meisenheimer complex and demonstrated that the decomposition of the MC is the rate

determining step. In substitution with ammonia preferential ortho-selectivity is realized in non

polar solvents and is relaxed with increasing solvent polarity. The nucleophilic aromatic



substitution (SNAr) reaction between azide ion and 4-fluoronitrobenzene has been

investigated using DFT calculations in protic and dipolar aprotic solvents [46]. The effects of

solvation on the transition structures, the intermediate Meisenheimer complex, and the rate of

reaction are elucidated. But the mechanism of displacement of aromatic halogen by primary

amines has not been explored using ab initio molecular orbital calculations. The method for

the synthesis of N-(2-nitroaryl)aminoethanol involves either the displacement of halogen

using ethanolamine [47,48] or the Smiles rearrangement of 2-(nitrophenyl)ethylamine [49].

The gas- phase reaction of fluoride ions with nitrobenzene has been investigated in gas phase

and very fast aromatic nucleophilic substitution is observed [50]. The mechanism of the

reaction is characterized by carrying out DFT calculations at the B3LYP/6-311++G

(d,p)//B3LYP/6-311++G(d,p)level of theory using the Gaussian 98 software package. The

DFT calculations are found to provide reasonably reliable estimates for the complexation

energies calculated at different levels of theory and the low local energy barrier found for the

nucleophilic displacement suggests that the nucleophilic aromatic displacement should be

fast, and its efficiency dictated by the density of states of the transition state.

.

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