Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups / 0423 477

10. Hydrogen bonding and complex formation

463

TABLE 1. Apparent stability constant Kc of complexes between aromatic amines and 1-fluoro-2,4-dinitrobenzene (unless otherwise indicated) at 40 °C

			Kc
Amine	Solvent	mol 1 dm3 b			Reference
Aniline	benzene	0.068			253
Aniline	chloroform	0.70			253
Anilinea	benzene	0.068a			253
Anilinea	chloroform	0.068a			253
Anilinea,c	ethanol	0.34a,c		(0.49)	256
Anilinea,c	ethanol/ethyl acetated	0.12a,c		(0.17)	256
Anilinea,c	ethyl acetate	0.05a,c			256
Aniline	tetrahydrofuran	0.20	(0.31)		257
2H-Aniline-d7e	chloroform	0.62e			253
N-Methylaniline	benzene	0.66			253
N-Methylaniline	tetrahydrofuran	1.06	(0.65)		257
N,N-Dimethylaniline	benzene	0.44			253
p-Methoxyaniline	benzene	0.67			253
p-Methoxyaniline	tetrahydrofuran	1.17	(1.58)		257
p-Methoxyaniline	chloroform	0.37			258
p-Methoxyaniline	carbon tetrachloride	1.5			258
p-Methoxyaniline	chlorobenzene	0.29			258
p-Methoxyaniline	1,2-dichloroethane	0.95			258
p-Methoxyaniline	1,4-dioxane	0.81			258
m-Methoxyaniline	benzene	0.055			253
m-Methoxyaniline	tetrahydrofuran	0.20	(0.43)		257
p-Methylaniline	benzene	0.24			253
p-Methylaniline	tetrahydrofuran	0.41	(0.31)		257
m-Methylaniline	benzene	0.11			253
m-Methylaniline	tetrahydrofuran	0.43	(0.16)		257
p-Chloroaniline	benzene	0.022			253
p-Chloroaniline	tetrahydrofuran	0.46	(0.29)		257

a1-Chloro-2,4-dinitrobenzene.

bCalculated from UV/VIS spectrophotometric analyses by Benesi Hildebrand treatment. Range of values used in the determination: from 410 to 450 nm. In parentheses: values calculated from kinetic data.

c At 23.8 °C.

d50:50, by volume.

eCalculated from 1H NMR data in CDCl3.

and 0.48 (mol 1 dm3) respectively, at 26 °C, with the electron donor partner being the

solvent in all cases254.
The main consequence of EDA interactions			between	solvents	of high	donicity
and nitroarenes is that amines	in benzene (or		in other	similar	solvents)	compete
with the solvents in complexing the		nitroarenes253,254. This fact			explains	the ratio
Kcchloroform/Kcbenzene D 10 for	the	molecular complex between aniline and FDNB

(see Table 1).

Table 2 shows some Kc values of equilibria like 29 between nitroarenes and aliphatic amines. Even if differences in the mechanism of interactions (as well as differences in experimental conditions, in particular solvents and temperature) make a full comparison difficult, some main points from data of Table 2 are worthy of consideration.

(i) The introduction of a fluorine atom on the nitro-containing substrate stabilizes the complex: KcFDNB > Kc1,3 DNB as required if the fluoro derivative interacts with amines by hydrogen bonding.

464	Luciano Forlani

TABLE 2. Apparent constant of stability of molecular complexes between nitroaromatic derivatives and aliphatic amines in various solvents

Substratea	Amine	Solvent	T °C	Kc mol 1 dm3 b	Reference
1,2-DNB	dibutylamine	n-hexane	27	0.25	255
1,2-DNB	tributylamine	n-hexane	27	0.098	255
1,3-DNB	n-butylamine	n-hexane	27	0.39	255
1,3-DNB	diethylamine	n-hexane	27	0.24	255
1,3-DNB	di-n-butylamine	n-hexane	27	0.20	255
1,3-DNB	triethylamine	n-hexane	27	0.089	255
1,3-DNB	tributylamine	n-hexane	27	0.043	255
1,4-DNB	n-butylamine	n-hexane	27	0.36	255
1,4-DNB	dibutylamine	n-hexane	27	0.17	255
1,4-DNB	tributylamine	n-hexane	27	0.032	255
FDNB	n-butylamine	toluene	21	14c	259
FDNB	n-butylamine	cyclohexane	21	27	260
FDNB	piperidine	cyclohexane	21	79	260
CDNB	piperidine	cyclohexane	21	3.4	260
CDNB	n-butylamine	cyclohexane	21	0.08	260
FDNB	DABCOd	benzene	25	0.31; (0.31)c	261
FDNB	TEe	benzene	40	0.47c	258
TNB	DBUf	toluene	18	12	245

a 1,2-DNB D 1,2-dinitrobenzene; 1,3-DNB D 1,3-dinitrobenzene; 1,4-DNB D 1,4-dinitrobenzene; FDNB D 1-fluoro-

2,4-dinitrobenzene; CDNB		D	1-chloro-2,4-dinitrobenzene; TNB		D	1,3,5-trinitrobenzene.
b
	Calculated from UV/VIS spectrophotometric data, unless otherwise indicated.
c Calculated from kinetic data.
d
e DABCO D 1,4-diaza[2.2.2]bicyclo-octane.
TE D triethylamine.				D 7.3 at 25 °C, 5.7 at 33 °C; HŁ			D 39 kJ mol 1, S D
f DBU D 1,8-diazabicyclo[5,4,0]undec-7-ene, Kc
357 J mol 1 K 1.

(ii)The stability order KcFDNB > KcCDNB for n-butylamine and piperidine indicates that a hydrogen bond is operating.

(iii)The presence of steric requirements for the formation of complexes is an important point to explain relative stabilities of complexes. The system aliphatic amines/dinitrobenzenes in hexane reveals the presence of an interaction, which is defined

as an electron donor acceptor (EDA) interaction255. The donor ability decreases by passing from primary amines (n-butylamine) to secondary amines (di-n-butylamine, diethylamine) and to tertiary amines (tri-n-butylamine and triethylamine) as indicated by the differences in stability of the complexes. The order Kcprimary > Kcsecondary > Kctertiary is explained by the steric requirements of the electron donor for the formation of the complexes which are usual when donor acceptor interaction is operating.

(iv) Piperidine is more prone to interacting with both FDNB and CDNB than n- butylamine (Kcpiperidine > Kcn-butylamine). Generally, cyclic secondary amines have less steric requirements than non-cyclic secondary amines.

The change in the relative positions of the nitro groups affords the trends 1,2- > 1,3- > 1,4-dinitrobenzene, for the stability of the complexes, but the observed differences are moderate.

Recently262, the apparent stability constants of the complexes between aromatic fluoro derivatives and amines (shown in equilibrium 31, Kc in mol 1 dm3) in toluene-d8 were evaluated by 19F chemical shift measurements.

ArF	C	HNRR0	Kc	Ð	31
				ArF HNRR0

10. Hydrogen bonding and complex formation

465

The main interaction of the complex of equilibrium 31 is probably a hydrogen bonding interaction between nitrofluorobenzenes and some amines. These complexes are more stable when the nitro groups are in position 2 of fluorobenzene than when they are in position 4. A reasonable explanation of this trend is the interaction of the ortho nitro group with the amine shown in 110, in which a second hydrogen bond (between the amino and the nitro groups) enhances the interaction.

For n-butylamine, the Kc2-nitrofluorobenzene/Kc4-nitrofluorobenzene ratio equals 4, while for the secondary amine piperidine the ratio is higher (Kc2-nitrofluorobenzene/Kc4-nitrofluorobenzene D 9). This supports an interaction between the two nitrogen atoms as shown in 111, where the nitrogen of the amine is the electron donor and the nitrogen of the nitro group is the electron acceptor.

	R		H
N			R
H	H	H	N
F	O−	F	O−
+N	O		N O
			+

(110)

(111)

The self-association of amines (see Section II.C) is a complication which is almost impossible to evaluate, in all the quantitatively studied systems involving protic amines, in associating solvents, including the data and observations reported here.

B. Some Kinetic Features of Aromatic Nucleophilic Substitution Reactions

The usual kinetic law for SNAr reactions is the second-order kinetic law, as required for a bimolecular process. This is generally the case where anionic or neutral nucleophiles react in usual polar solvents (methanol, DMSO, formamide and so on). When nucleophilic aromatic substitutions between nitrohalogenobenzenes (mainly 2,4- dinitrohalogenobenzenes) and neutral nucleophiles (amines) are carried out in poorly polar solvents (benzene, hexane, carbon tetrachloride etc.) ‘anomalous’ kinetic behaviour may be observed263. Under pseudo-monomolecular experimental conditions (in the presence of large excess of nucleophile with respect to the substrate) each run follows a first-order

kinetic law, but the rate constants (kobs in s 1 mol 1 dm3) were not independent of the initial concentration value of the used amine. In apolar solvents the most usual kinetic

feature is the increase of the kobs value on increasing the [amine]0 values; [amine]0 indicates the initial concentration value of the amine.

This kinetic feature is observed by using primary and secondary amines, both aromatic and aliphatic. Tertiary amines263 (and other substances unable to produce substitution products such as 2-hydroxypyridine264) may act as a catalyst: in apolar solvents, in a series of runs carried out without changing the initial concentration value of substrate and of amines, it was found that the addition of tertiary amines enhances kobs values.

In more polar solvents, as reported in 1954 by Ross and Kuntz256, for reactions between 2,4-dinitrochlorobenzene and aniline, kobs values decrease with increasing [amine]0 values. A possible interpretation of this kinetic feature is the formation of a molecular compound between aniline and 2,4-dinitrochlorobenzene by a quickly established equilibrium, which

466	Luciano Forlani

precedes the substitution process. In principle, such complex kinetic features are usually attributed to the presence of some equilibria preceding the reactions and involving the reactants and the solvent265,266.

It is known that when the kinetic behaviour cannot be studied in the absence of the molecular complex (and the reactivity of the free reagent is unknown), the kinetic law by itself cannot indicate whether the complex observed is on the reaction pathway or is a non-productive equilibrium267. In SNAr reactions discussed here, the usual experimental conditions [ArF]0 < [RNH2]0 are used. In some cases, the kobs values obtained under experimental conditions [ArF]0 > [RNH2]0 may be assumed to involve only the uncatalysed process. As a consequence, it is possible to say that the presence of complexes (in apolar solvent) clearly produces an enhancement of the reactivity and a positive catalysis, while in polar solvents256 the presence of complexes depresses the rate of substitution.

Scheme 14 has long been considered263,268 the explanation of this kinetic behaviour with the intervention of a second molecule of catalyst (or of the same reacting amine) on the zwitterionic intermediate to promote the departure of the proton and of the leaving group.

+

NHRR′

	k1	−	k2
ArL + HNRR′		Ar		ArNRR′ + HL

k −1

L k3

catalyst

SCHEME 14

The more popular mechanism of HL elimination263 (where L is the leaving group) is the SBGA mechanism (Specific Base General Acid) which involves a base-catalysed abstraction of the proton and the acid catalysed departure of the leaving group from the zwitterionic intermediate 112 (where G are electron-withdrawing groups) of the usual twostep mechanism of SNAr reactions. In some cases, a concerted mechanism of departure of the proton and the leaving group is operating.

N

H H

+

L N

−

G

(112)

On the basis of the presence of the molecular complexes discussed in the previous section and of other observations253,260, Scheme 15 was proposed as an alternative to the more usually accepted mechanism shown by Scheme 14. The left part of Scheme 15 is the uncatalysed reaction pathway, while the part on the right is the catalysed one.

10. Hydrogen bonding and complex formation										467
			Catalyst (HNRR′)
ArL				Kc			Molecular Complex
		+ HNRR′					+ HNRR′
k°−1 k°1							k1 k−1
	zwitterionic					zwitterionic
	intermediate					intermediate
			k°2				k2

Products

SCHEME 15

Equation 32 is derived from Scheme 15 and allows the evaluation of Kc values reported (in parentheses) in Tables 1 and 2.

kobs 1 C Kc[RNH2]0 D k0 C Kck[RNH2]0

32

By considering k D k1/k 1 k2 and k0 D k10/k 10 k20, the first condition to observe catalytic behaviour is that k > k0. Obviously when k0 D k, no effect of the variation in the initial amount of amine may be detected and kobs is an actual second-order rate constant; when k0 < k, a decrease in kobs values on increasing [RNH2]0 values may be observed.

When Kc[RNH2]0is − 1, k0 (for low values of initial amine concentration when fluoro derivatives are used, or when Kc is a low value as in cases of chloro derivatives), kobs is k0 (the uncatalysed process). When Kc[RNH2] becomes a high value (because [RNH2] is increased), there is a leveling-off of the rate as shown in Figure 1.

The general overall kinetic behaviour of Figure 1 may be observed (under the experimental conditions [ArF]0 < [RNH2]0) if a large range of concentration values of amine is used, as in the case of the reactions between 2,4-dinitro-fluorobenzene and n-butylamine in benzene269 or toluene259. The major part of cases reported in the literature concerns a more restricted range of [amine]0 values.

The first horizontal part of the plot of Figure 1 (A) corresponds to the substitution process in the absence of catalysis, kobs D k0. Consequently, it allows the evaluation of the reactivity of the ‘free’ substrate. This value is confirmed by runs carried out under experimental conditions [ArF]0 > [RNH2]0 (which are unusual in these investigations): the same kobs value is obtained, in agreement with a second-order kinetic law, for reaction of ‘free’ substrate.

The second part (B) of the plot is referred to the presence of both processes: the substitution reaction of the ‘free’ substrate and the reaction of the complexed substrate. The plateau (C) is a leveling-off of the rate and corresponds to the saturation of the catalytic process: in this range of [RNH2]0 values the main reaction is that of the complexed substrate.

A very interesting (and important) detail of the SNAr reaction showing positive catalysis is the dependence of catalysed and uncatalysed processes on the temperature and was investigated in several instances270 274. There are systems271,272 in which the experimental reaction rate constant (in s 1 mol 1 dm3) is decreased on increasing the temperature. In other instances the increase in the temperature doesn’t have an effect on kobs273.

468	Luciano Forlani

kobs

(s−1 mol−1dm3)

(C)

0.5

(B)

(A)

[RNH2]0 (mol dm−3)

0

0

0.002

0.2

FIGURE 1. Diagram to show the effect of the increase in the initial concentration value of amine on the rate of substitution expressed as a second-order rate coefficient. Indicative [RNH2]0 values and kobs values are from reactions between 2,4-dinitrofluorobenzene and n-butylamine in toluene259

In the case of the reactions between 1,3,5-trinitrobenzene (TNB) and 1,8- diazabicyclo[5,4,0]undec-7-ene (DBU)245, in toluene, shown in Scheme 16, regarding the formation of a zwitterionic -complex, kobs values are increased on increasing the [DBU]0 values: there is a catalytic effect of the base in a system without leaving group and proton. The increase in kobs values is related to the presence of the molecular complex between TNB and DBU indicated by Scheme 16.

Analysis of the data allows the observation that the substrate/nucleophile association (Kc values, see Table 2) is clearly decreased on increasing the temperature, while the k1 and k10 of Scheme 16 (the attack of the DBU on the ‘free’ TNB and on the complexed TNB, respectively) are increased on increasing the temperature, showing activation parameters usual in SNAr reactions.

The reaction of 1-fluoro-2,4,6-trinitrobenzene and 2,4-dimethoxyaniline, in cyclohexane, shows a negative activation enthalpy274 ( 30 kJ mol 1), in agreement with a ‘desolvative association mechanism’ in which the nucleophile competes with the solvent in associating with the substrate in an equilibrium preceding the substitution process.

The reactions 33 between tetrachloro-N-n-butylphthalimide (113) and n-butylamine275 in aprotic and apolar media (cyclohexane, benzene, toluene, xylenes) show a third experimental reaction order in the amines explained by the formation of a complex (n -like) between the electron acceptor substrate (the derivative of the phthalimide) and the electron donor nucleophile (the amine). In mixed solvents (such as the mixtures cyclohexane/aromatic solvents) the kinetic investigation reveals the presence of a competition between the electron donor solvent and the amine in complexing the substrate.

10. Hydrogen bonding and complex formation						469
TNB	+ DBU	Kc		[molecular complex]
	k°1 k°−1			k −1	+ DBU
					k1
				N
			+
		H		N
	O2 N			NO2
			−
			NO2
	SCHEME 16
Cl	O
Cl	C
	N(CH2 )3 CH3 + H2 N(CH2 )3 CH3
Cl	C
	O
Cl
(113)						(33)
				Cl	O
		Cl			C
					N(CH2 )3 CH3
					N(CH2 )3 CH3
		Cl			C
				Cl	O

Another reaction mechanism explaining the observed enhancement of kobs values with increasing [amine]0 values in SNAr reactions is the ‘dimer mechanism’276, which involves the self-association of the amines277 279 and which (in some cases) may be considered overlapped with mechanism of Scheme 14. A reaction pathway for ‘dimer mechanism’ is shown in Scheme 17. Considering the zwitterionic intermediate 114 it is possible to have a catalysis in removing the proton and the leaving group (reaction pathway indicated

by k3).

On the other hand, it is reasonable to admit that several different mechanisms may be in competition to afford the products of the reaction. Under particular experimental conditions, a mechanism may predominate over another with a specific reaction pathway;

470

Luciano Forlani

H

R

N .....

H

H

H .

H

..

.

+NHR

k1

. L

k2

O2 N

L + RN

H

NR

NO2

Products

k−1

H

−

k3

NO2

Catalyst

NO2

(114)

SCHEME 17

in other cases, depending on the experimental conditions, another reaction pathway may be the one leading to the final product.

Anyway, it is important to remember that a mechanism may hardly be demonstrated: a mechanism is a scientific theory which may be proved false by further observations280. In principle, our data are only able to give us some indications to the possible pathways of the reactions.

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