Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups / 0479 531

11. Electronic effects of nitro, nitroso, amino and related groups				489
−O2 N	+	O2 N +	CO2 − H
	NH2
(13)			(14)

activated complex, which resembles the carbocation chloride ion pair, through delocalization involving structure 15. Such delocalization will clearly be more pronounced than in the species involved in the ionization of p-methoxybenzoic acid, which has a reaction centre of feeble CR type (16). The effective value for p-OMe in the solvolysis of t- cumyl chloride is thus 0.78, compared with the value of 0.27 based on the ionization of benzoic acids.

+	CMe2 Cl−			+		CO2 − H
MeO			MeO
	(15)					(16)
The special substituent constants for		C	R para-substituents are denoted by , and
				82	. They are based respectively on the
those for R para-substituents are denoted by C

reaction series discussed above. Selected values are given in Table 1. Characteristic orC values are sometimes distinguished for meta-substituents also, but only for a minority of substituents which show very marked CR or R effects do these differ significantly from ordinary values. The range of applicability of the Hammett equation is greatly extended by means of and C, notably to nucleophilic (by ) and to electrophilic (by C) aromatic substitution.

However, the ‘duality of substituent constants’ and the attempt to deal with crossconjugation by selecting C, or in any given case is somewhat artificial. The contribution of the resonance effect of a substituent relative to its inductive effect must in principle vary continuously as the electron-demanding quality of the reaction centre is varied, i.e. the extent to which it is electron-rich or electron-poor. A ‘sliding scale’ of substituent constants would be expected for each substituent having a resonance effect and not just a pair of discrete values: C and for R, or and for CR substituents83.

B. Multiparameter Extensions75,76,84

There are two main types of treatment, both involving multiparameter extensions of the Hammett equation, which essentially express the ‘sliding scale’ idea.

In the Yukawa Tsuno equation (1959)85 (equation 3), the sliding scale is provided by multiple regression on and ( C ) or ( ), depending on whether the reaction is more or is less electron-demanding than the ionization of benzoic acid. (There is a corresponding equation for equilibria.) The quantity rš gives the contribution of the enhanced šR effect in a given reaction. (The equation was modified in 196686 to use 0 instead of values, see below, but the essential principles are unaltered.)

log k D log k0 C [ C rš š ]

3

In the form of treatment developed by Taft and his colleagues since 195687 89, the Hammett constants are analyzed into inductive and resonance parameters, and the sliding scale is then provided by multiple regression on these. Equations 4 and 5 show the basic

490	John Shorter

relationships, the suffix BA signifying benzoic acid. The I scale is based on alicyclic and aliphatic reactivities (see below), and the factor 0.33 in equation 4 is the value of a ‘relay coefficient’, ˛, giving the indirect contribution of the resonance effect to m. However, the ionization of benzoic acids is not regarded as an entirely satisfactory standard process, since it is subject to some slight effect of cross-conjugation (see structure 16 above). Consideration of ‘insulated series’, not subject to this effect, e.g. the ionization of phenylacetic acids, is used as the basis of a 0 scale, which can be analyzed by equations 6 and 790. (Note the different value of ˛.) By a different procedure Wepster and colleagues83 devised an analogous n (n D normal, i.e. free from the effects of cross-conjugation). Analysis of C and constants correspondingly involves RC and R .

m	D I C 0.33 R(BA)	(4)
p	D I C R(BA)	(5)
m0	D I C 0.5 R0	(6)
p0	D I C R0	(7)

Multiple regression on I and R-type parameters employs the ‘dual substituentparameter’ equation, which may be written as in equation 891. (The combining of the k and k0 terms implies that there is no intercept term allowed, and k0 is now the actual value for the parent system, cf below.) For any given reaction series the equation is applied to meta- and para-substituents separately, and so values of I and R characteristic both of reaction and of substituent position are obtained. The various R-type scales are linearly related to each other only approximately. In any given application the scale which gives the best correlation must be found92.

logk/k0 D I I C R R 8

Values of 0, I and R-type parameters for certain substituents are given in Table 2. It should be mentioned that Exner has developed a slightly different procedure for analysing sigma values93 into inductive and resonance components76,77,94.

A slightly different procedure for carrying out multiple regression on I and R-type parameters employs the ‘extended Hammett equation’ of Charton95, which may be written as in equation 9. For the substituent X, Q is the absolute value of the property to be correlated (log k or log K in the case of reactivity), i.e. not expressed relative to X D H, h is introduced as the appropriate intercept term, and the regression coefficients are ˛ and

ˇ. (Charton has used various symbols at various times.)
			Q D ˛I,X C ˇR,X C h						9
TABLE 2.	Selected valuesa of 0, I and R-type constants
Substituent	m0	p0	I	R(BA)	R0	RC			R
Me	0.07	0.15	0.05	0.12	0.10	0.25
OMe	0.06	0.16	0.26	0.53	0.41	1.02
NO2	0.70	0.82	0.63	0.15	0.19				0.61
F	0.35	0.17	0.52	0.46	0.35	0.57
Cl	0.37	0.27	0.47	0.24	0.20	0.36

aSee footnote to Table 1. The values for NO2 will be discussed later in this chapter.

11. Electronic effects of nitro, nitroso, amino and related groups

491

The correlation analysis of spectroscopic properties in terms of I and R-type parameters has been very important. Substituent effects on 19F NMR shielding in fluorobenzenes have been studied in great detail by Taft and colleagues90,96,97. For υFm linear regression on I is on the whole satisfactory, but a term in R0 with a small coefficient is sometimes introduced. The correlation analysis of υFp, however, requires terms in both I and R-type

parameters, with R0 being widely applicable. Many new values of these parameters have been assigned from fluorine chemical shifts. In recent years there has also been extensive use of correlation analysis of 13C NMR data98,99.

The correlation analysis of infrared data has been much examined by Katritzky, Topsom and colleagues100,101. Thus the intensities of the 16 ring-stretching bands of monoand di-substituted benzenes may be correlated with the R0 values of the substituents and these correlations may be used to find new R0 values.

Finally, in this account of multiparameter extensions of the Hammett equation, we comment briefly on the origins of the I scale. This had its beginnings around 195689 in the 0 scale of Roberts and Moreland102 for substituents X in the reactions of 4-X- bicyclo[2.2.2.]octane-1 derivatives. However, at that time few values of 0 were available. A more practical basis for a scale of inductive substituent constants lay in the Ł values for XCH2 groups derived from Taft’s analysis of the reactivities of aliphatic esters into polar, steric and resonance effects89,103 105. For the few 0 values available it was shown that0 for X was related to Ł for XCH2 by the equation 0 D 0.45 Ł. Thereafter the factor 0.45 was used to calculate I values of X from Ł values of XCH2106. These matters will be referred to again later in this chapter, and other methods of determining I values will also be mentioned. Taft’s analysis of ester reactivities was also important because it led to the definition of the Es scale of substituent steric parameters, thereby permitting the development of multiparameter extensions of the Hammett equation involving steric as well as electronic terms.

III. ELECTRONIC EFFECTS OF THE NITRO GROUP ON THE STRENGTHS OF

CARBOXYLIC AND OTHER ACIDS107

A. Alicyclic, Aliphatic and Related Systems

The simplest indicator of the electronic effect of a substituent X is its influence on the ionization constant of an organic acid into which it is substituted. For the least complicated behaviour, the group should not be conjugated with the molecular skeleton and should not be too close to the acidic centre. The change in acid strength produced by X is conveniently expressed as pKa, defined as pKa H pKa X, so that an increase in acid strength is associated with a positive value of pKa. In Table 3 the pKa value of 1.05 for 4-nitrobicyclo[2.2.2]octane-1-carboxylic acid (17) (in 50% w/w EtOH H2O at 25 °C) and of 3.48 for the 4-nitroquinuclidinium ion (18) (in water at 25 °C) are clear indications

NO2	NO2
	N+
COOH	H
(17)	(18)

492		John Shorter
TABLE 3. The influence of the nitro group on the strengths of alicyclic and related acids107
							Temp.	pKa	pKa		Ib
Acid		Solvent					(°C)	X D H	X D NO2	pKaa	(calc)
1.	4-X-Bicyclo[2.2.2]octane-	50% w/w EtOH				H2O	25	6.87	5.82	1.05	0.673c
	1-carboxylic acid
2.	4-X-Quinuclidinium ion	H2O					25	11.12	7.64	3.48	0.642
3.	9-X-10-Triptoic acid	50% w/w EtOH				H2O	25	5.20	4.40	0.80	0.681
4.	9-X-10-Triptoic acid	80% w/w MCS			H2O		25	6.23	5.43	0.80	0.683
5.	3-X-Adamantane-1-	50% v/vd EtOH				H2O	25	6.90	6.00	0.90	0.655
	carboxylic acid

a pKa D pKa H pKa NO2 .

bFrom the appropriate regression equations in Charton’s review109. c By definition, see text.

di.e. a solvent made up from equal volumes of ethanol and water. See further in Section III.C, Reference 126.

of the electronegative or electron-attracting nature of NO2. The influence of this reaches the acidic centre by induction through the bonds of the molecular skeleton or through the electric field of the substituent as moderated by the dielectric behaviour of the molecular cavity and the solvent. The respective roles of these two modes of transmission have long been a matter of controversy108. Both are ‘inductive’ in the most general meaning of the term in physics and we shall continue the traditional practice of describing them collectively as the ‘inductive effect’.

Data for the bicyclooctane system in 50% w/w EtOH H2O are the basis for primaryI values according to Charton109, calculated through equation 10110.

I D pKa/1.56

10

This procedure gave a value 0.673 for I of the nitro group, which was rounded to 0.67. The available values of I (including that for NO2 as 0.67 and ‘secondary’ values for certain substituents109) were used by Charton to establish regression equations of the general form of equation 11:

pKa D LI C h

11

for systems 2 to 5 in Table 3111. The back-calculated values of I for NO2 are shown in the last column of the Table. The range of values from about 0.64 to 0.68 indicates that the value of 0.67 is reasonably applicable throughout these rather varied systems (18 to 20). It should be noted, however, that the data points for NO2 exert a strong influence on the regressions, since at I D 0.67, NO2 is at one extreme of the scale for the substituents involved. For comparison we mention I values as follows: CF3, 0.40; Cl, 0.47; CN, 0.57.

COOH

NO2

NO2

COOH

(19)

(20)

11. Electronic effects of nitro, nitroso, amino and related groups

493

In his work ca 1956 based on the analysis of substituent effects in aliphatic ester reactions, Taft87,89 derived Ł D 1.40 for CH2NO2, which gave I D 0.63 by application of the equation I D 0.45 Ł (see Section II.B). In 1964, however, Charton112 derived the considerably higher value of 0.76 for I of NO2. This was based on a regression of the pKa values of substituted acetic acids in water at 25 °C against the I values of the substituents. There is a similar regression in his 1981 review109,113. If the pKa value of nitroacetic acid is taken as 1.655 (the mean of two reasonably concordant values in the literature107c) and inserted into this regression113, a I value of 0.77 for NO2 is obtained, close to Charton’s earlier value112. In Charton’s 1981 review109 the pKa values of substituted acetic acids are used as a secondary source of I values, but this has to be done circumspectly, because of the possibility of additional effects arising from the mutual proximity of substituent and carboxyl groups. Such effects may notably be steric in nature or may involve internal hydrogen bonding. In the case of the nitro group it appears that the nett influence of such effects is slightly to increase the acidity of the carboxyl group. The pKa value of ˇ-nitropropanoic acid is 3.79 at 25 °C in water. If this value be inserted into the regression for substituted acetic acids, a I value of 0.247 for CH2NO2 is obtained. This shows the ‘damping’ effect of the CH2 group, for which a decremental factor of about 2.7 has been suggested89. On this basis the I value of NO2 may be calculated from the above value for CH2NO2 as 0.247 ð 2.7 D 0.667, in good agreement with the value based on the bicyclooctane system, as discussed above.

B. Aromatic Systems

Measurements of the dissociation constants of m-nitrobenzoic acid and p-nitrobenzoic acid began with Ostwald in 1889114. However, the first reasonably precise values were obtained by Dippy and coworkers in the nineteen-thirties, as part of an extensive study of the ionization of carboxylic acids by conductimetric methods115. The pKa values in water at 25 °C of m-nitrobenzoic acid and p-nitrobenzoic acid were found to be 3.493 and 3.425, respectively, compared with 4.203 for benzoic acid itself. On the basis of these values Hammett28,116 proposed values of 0.710 for m-NO2 and 0.778 for p-NO2 (see Section II.A). These values have commonly been used thereafter, often rounded to 0.71 and 0.78, respectively.

The marked acid-strengthening effect of p-NO2 is usually attributed to the influence of the electron-attracting inductive effect (CI), augmented by a small electron-attracting mesomeric or resonance effect (CR). The smaller acid-strengthening effect of m-NO2 is explained as the resultant of the inductive effect and a small ‘relayed’ influence of the resonance effect. If p is regarded simply as a sum of I and R (Section II.B) and I is taken as 0.67 (Section III.A), a value of 0.78 0.67 D 0.11 is indicated for R. The relay factor of 0.33 for the resonance effect accounts reasonably well for the value of m as I C 0.33 R D 0.67 C 0.04 D 0.71; cf 0.71 above.

During the past half-century the pKa values of m- and p-nitrobenzoic acids have been redetermined by several research groups, employing various experimental methods, including conductimetric, electrometric and spectrophotometric methods. The results have recently been considered by a Working Party on the Compilation and Critical Evaluation of Structure Reactivity Parameters under the auspices of the Commission on Physical Organic Chemistry of the International Union of Pure and Applied Chemistry79. The values derived from the individual redeterminations all agree fairly closely with those proposed by Hammett28,116. Detailed consideration leads to weighted mean values of 0.734 for m-NO2 and 0.777 for p-NO2, to be rounded to 0.73 and 0.78, respectively, for most purposes in correlation analysis, i.e. the new value for p-NO2 is effectively identical to the old value, but the new value for m-NO2 is 0.02 units higher than the old. Such

494	John Shorter

values for m- and p-NO2 appear to be reasonably well applicable to reactions of benzoic acid and its derivatives in aqueous organic solvents. However, the application of the simple classical Hammett equation should always be approached with circumspection. The possibility of solvent effects on values should be borne in mind, and also the possible intervention of hydrophobic effects of substituents, which may mimic electronic effects. The importance of hydrophobic effects in influencing reactivity has only been realized in recent years. Such effects have been discussed in detail by Hoefnagel and Wepster117 and have been expressed in terms of Hansch’s hydrophobic substituent constant 118. The value of NO2 is modest at 0.28, cf CN, 0.57; Cl, 0.71; CF3, 0.88: But, 1.98; and under most circumstances substituent hydrophobic effects will be of minor significance in the case of NO2. (For a brief introduction to substituent hydrophobic effects on reactivity, see the account of OPh in a previous article in this series119.)

In recent years Pytela and coworkers120 have obtained indications of a solvent effect onm and/or p for NO2. This research group determined the apparent pKa values for a large number of substituted benzoic acids in one-component organic solvents121. Their results for m- and p-nitrobenzoic acids are most easily discussed in terms of the relative order of the pKa values. In MeOH or EtOH the pKa values are in the order m-NO2 > p-NO2, as in water, but in DMF or sulpholane the order is m-NO2 < p-NO2. These relationships suggest that there may be a reversal of the order of the values in aprotic solvents, which would probably be connected with the absence of hydrogen bonding of the solvent to the O of NO2. This could be seen as diminishing the CR effect. Unfortunately, however, the pKa values determined in DMF or sulpholane are not very reproducible, and the mean errors quoted are of such a size as to cast doubt on the reality of the reversal of the pKa values. Further, the reversal does not occur with acetonitrile or acetone as solvent, but again the mean errors quoted are rather large. It is interesting, however, that a tendency to reversal is also found for certain solvents when the substituent is CN or SO2Me.

The electron-attracting effect of a p-nitro group is somewhat reduced by the presence of bulky groups in the adjacent positions. This is shown most simply by the effect of inserting flanking 3- and 5-methyl groups into 4-nitrobenzoic acid. The pKa values of 4-nitro-, 3-methyl- and 3,5-dimethyl-benzoic acids in 44.1% w/w EtOH H2O, 25 °C, are respectively as follows: 1.25, 0.17 and 0.80. If the effect of the groups in the 4-nitro- 3,5-dimethyl acid is strictly additive, its pKa value should be 1.25 2 ð 0.17 D 0.91. The observed effect is 0.80 and this indicates that the acid-strengthening effect of 4-NO2 is appreciably reduced by the flanking methyl groups. This is usually attributed to an inhibition of the resonance effect of the NO2 group by the methyl groups twisting it out of the plane of the benzene ring, thus making the p orbital overlap of NO2 and ring less effective. However, the interpretation of the above results for NO2 in terms of steric inhibition of resonance is not everywhere accepted122,123.

C. Acids of the Type Ph−G−COOH

It was mentioned in Section II.B that the ionization of benzoic acids is not regarded as an entirely satisfactory standard process, since in the case of R substituents, such as OMe, it is subject to some slight effect of cross-conjugation (see structure 16). Consideration of ‘insulated series’, not subject to this effect, e.g. the ionization of phenylacetic acids, is used as the basis of the 0 scale. For the sake of uniformity 0 values for CR substituents have also been based on such systems. Wepster and colleagues124,125, however, have criticized the use of systems in which the substituent is ‘insulated’ by methylene groups from the reaction centre for its tendency to lead to slightly exalted values of 0 for CR substituents, i.e. the supposed insulation is not 100% effective. They see an analogy to the very pronounced exaltations that occur in the effects of CR substituents on the

11. Electronic effects of nitro, nitroso, amino and related groups										495
TABLE 4. The influence of the nitro group on the strengths of acids of the
type Ph G COOH in 50% v/v EtOH				H2O, 25 °C124			126
	pKaa	pKaa					m	p
G	m-NO2	p-NO2					(calc)	(calc)
CH2	0.49	0.61			0.71	0.69		0.86
CH2CH2	0.24	0.31			0.36	0.67		0.86
CMe2CH2	0.27	0.36			0.38	0.71		0.95
NHCH2	0.24	0.50			0.38	0.63		1.32
NHCH2CH2	0.17	0.29			0.23	0.74		1.26
OCH2	0.38	0.51			0.52	0.73		0.98
SCH2	0.36	0.56			0.51	0.71		1.10

a pKa D pKa H pKa NO2 .

ionization of Ph G COOH with G D NHCH2, OCH2 or SCH2. It is suggested that CH2 is capable of a slight R interaction with the benzene ring through its hyperconjugation and this can lead to cross-conjugation with a CR substituent. If this view be accepted, for CR substituents it is better simply to assume that values based on benzoic acid ionization are effectively values of 0, since COOH shows a CR effect and there can be no cross-conjugation. This has been done explicitly in a recent compilation by Exner77.

The above points will now be illustrated with respect to the nitro group. The most convenient data for this purpose are for ionization in 50% v/v EtOH H2O124 126. (Data for other solvent compositions are also in the References124,125.) pKa values for the effects of m- and p-NO2 on the various acids Ph G COOH, along with the corresponding Hammett values (Section II.A), are shown in Table 4. The values of m (calc) and p (calc) are obtained as (calc) D pKa/ .

The data for most of the systems give values of m(calc) reasonably close to the value of m for NO2 on the benzoic acid-based scale, as discussed in Section III.B. In fact, excluding the N-phenylglycine system, which may be complicated by zwitter-ion formation, the mean value for m(calc) is 0.71. However, the values of p(calc) for the effects of NO2 in the phenylacetic and 3-phenylpropanoic acid systems are appreciably greater than the benzoic acid-based value of 0.78 (Section III.B). This supports the views of Wepster and colleagues124,125 that cross-conjugation between a CR substituent and methylene, as in structure 21, may enhance the electron-attracting effect of the substituent. While it is possible that such enhancement might be due to a specific influence of solvent, no enhancement is apparent in the corresponding data for p-nitrobenzoic acid: pKa D 1.19, D 1.50; therefore p(calc) D 0.79117. The behaviour of p-NO2 in 3-methyl-3- phenylbutanoic acid indicates enhancement of the electronic effect, presumably through C C hyperconjugation involving the methyl groups. The enhancement is even more marked in the acids involving NH, O or S as part of G, conjugation of the lone pair electrons of N, O or S doubtless being involved, e.g. structure 22. The p(calc) values for NO2 in cross-conjugation with NH, O or S appear to be comparable overall with thep value of about 1.25 (Section III.D).

O2 N		−O2 N	H+
	CH2 COOH		CHCOOH
		(21)

496	John Shorter
		−O2 N	H +
O2 N	NHCH2 COOH		NCH2 COOH

(22)

D. Phenol and Anilinium Ion

The ionization of phenol and anilinium ion are both processes which are greatly facilitated by CR para-substituents such as NO2, SO2Me, CN, etc. (Section II.A). The values are most reliably determined by linear regression of pKa on for the meta-substituted substrates only, and the following equations 12 and 13 are typical127. (pKa values are for solutions in water at 25 °C.)

Phenols

		pKa D 9.936		C 2.205						(12)
				(š0.078)
		n D 9, r D 0.9957, s D 0.0579,					D 0.105
Anilinium ions
		pKa D 4.567		C 2.847						(13)
				(š0.079)
		n D 11, r D 0.9965, s D 0.0603,					D 0.092
	n		D number of data points,		r		coefficient, s		D	standard
(In these regressions						D correlation128,129
deviation of estimate,			D Exner’s statistic of goodness of fit					.) The insertion of

observed pKa values for the meta-nitro-substituted compounds (8.39 and 2.47, respectively) into the above expressions gives apparent values of m for NO2 as 0.70 and 0.74, respectively. These values are close to the benzoic acid-based value of m for NO2 (Section III.B). However, the corresponding insertion of pKa values (7.15 and 1.00, respectively) for the para-nitro-substituted compounds gives apparent values of p for NO2 as 1.26 and 1.25, respectively. These values are considerably enhanced from the benzoic-acid-based value of 0.78. The explanation for this enhancement is in terms of cross-conjugation, as given in Section II.A.

Such enhanced sigma values for CR groups are commonly designated as values. In the case of NO2, Exner78 tabulates two values of p from phenol ionization (1.28 and 1.24) and two values from anilinium ionization (1.23 and 1.25). The good agreement between these several determinations suggests that 1.25 should be a fairly reliable value for of NO2. Such good agreement between the phenoland anilinium-based values is rather unusual and an inspection of Exner’s compilation78 reveals a number of groups for which discrepancies of about 0.1 unit or more exist as between the two scales130. This provides a warning that the values based on the two systems should not be mixed in correlations. Ideally only one of these systems should be chosen as the basis for the scale. The other should be regarded as a system for treatment by the Yukawa Tsuno equation85,86 or other multiparameter extensions84 of the Hammett equation (Section II.B).

Further light is shed on the behaviour of CR substituents in phenol by studies of gas-phase acidity. Fujio, McIver and Taft131 measured the gas-phase acidities, relative to

11. Electronic effects of nitro, nitroso, amino and related groups

497

phenol, of 38 meta- or para-substituted phenols by the ion cyclotron resonance (ICR) equilibrium constant method. The results were treated by linear free-energy relationships and comparisons were made with the behaviour in aqueous solution. The present author has summarized elsewhere the salient features of this work132. We will restrict the present discussion to CR substituents. For NO2 the apparent value of m in the gas phase is 0.72, which the authors regard as essentially the same as the value in aqueous solution. However, p (g) is 1.04, compared with 1.23 quoted as the value of p (aq). For several other CR substituents, e.g. CN and SO2Me, p (g) is also lower than p (aq).

The most important inference from this situation is that131 ‘the previously generally held view that p (aq) values represent the inherent internal -electron-acceptor ability of CR substituents must be incorrect. Instead, p (aq) values are shown to involve a complex composite of field/inductive, internally enhanced -electron delocalization, and specific substituent HBA solvation assisted resonance effects’. Thus, while the enhancement of the electron-attracting effect of NO2 by hydrogen bonding to water is practically nil in the meta position, it is substantial in the para position because of the delocalization of charge from O into the substituent in the anion. The situation may be represented schematically as in structure 23.

O

H

H	δ′_
	O	δ	_
	N	O	(H2 O)3
	O δ′_
H

H

O

(23)

The influence of flanking methyl groups which was noted above (Section III.B) for the benzoic acid system is more marked in phenol ionization. The pKa values of 4-nitro- and 3,5-dimethyl-phenol (compared with phenol itself) are 2.78 and 0.19, respectively (water, 25 °C)133. Thus the pKa(calc) value for 4-nitro-3,5-dimethylphenol, assuming strict additivity, is 2.59, compared with pKa(obs) D 1.75, indicating marked steric inhibition of resonance through twisting the NO2 out of the plane of the ring by the methyl groups.

The effect of 4-NO2 on the acidity of phenol is somewhat enhanced by the introduction of methyl groups in the 2,6 positions134. Thus, pKa values for 4-nitro- and 2,6-dimethylphenol are 2.78 and 0.59, respectively133, giving pKa(calc) for 4-nitro- 2,6-dimethylphenol as 2.19. pKa(obs) is in fact 2.77. This enhancement is no doubt due to steric inhibition of the solvation of the O in the phenate ion, which increases sensitivity to the electronic effects of the substituents, i.e. the value. This effect is even more marked in 2,6-di-tert-butylphenol, for which the pKa value (relative to phenol) is3.06 (1:1 v/v EtOH H2O, 25 °C)134. In this system pKa for the 4-NO2 compound is 6.73, relative to 2,6-di-tert-butylphenol, corresponding to a value of about 5, compared with 2.9 for the ionization of phenol itself in the same solvent.

498	John Shorter

IV. THE ORTHO-EFFECT OF NO2

A. Introduction

The term ortho-effect has long been used to cover the peculiar influence of a substituent in the position ortho to a reaction centre, which often differs markedly from that of the same substituent in the meta- or para-position104,135,136. Steric phenomena have long been recognized as playing a major part in the ortho-effect. Primary steric effects of various kinds, including steric hindrance to the approach of the reagent or to solvation, and secondary steric effects have been invoked. In certain systems hydrogen-bonding and other intramolecular interactions have been postulated.

One of the main difficulties in understanding the ortho-effect, however, lies in adequately specifying the electronic effects of ortho-substituents. The relative contributions of I and R effects to the influence of ortho-substituents are liable to be very different from those operating at the meta- or para-position. There have been many attempts to develop scales of ‘sigma-ortho’ constants analogous to , 0, C , , etc. (Section II) for the meta- and para-positions, but such scales are never found to be of very general application104,136. The composition of the electronic influence of ortho-substituents with respect to I and R effects seems greatly subject to variation with the nature of the reaction, the side-chain, the solvent, etc. The inductive effect of an ortho-substituent operates at much shorter range than that of a meta- or para-substituent, but the orientations of substituent dipoles with respect to the reaction centre are very different from those of meta- or para-substituents. It is sometimes supposed that the resonance effect of an ortho-substituent tends to be inherently weaker than that of the same substituent in the para-position, because ortho-quinonoid instead of para-quinonoid structures may be involved in its operation. However, the resonance effect also is being delivered at rather short-range from the ortho-position.

The most fruitful treatment of the electronic effects of ortho-substituents involves the use of the same I and R-type constants as may be employed in correlation analysis for meta- and para-substituents by means of the ‘dual substituent-parameter equation’91 or the ‘extended Hammett equation’95 (Section II.B). Obviously it is a considerable assumption that these are valid for ortho-substituents and the implication is that in the correlation analysis any peculiarities may be adequately expressed through the coefficients of the inductive and resonance terms. Really satisfactory correlation analysis for any given reaction system requires a large amount of data and can only rarely be accomplished.

In Section IV.B we will discuss the ortho-effect of NO2 as manifested in the ionization of carboxylic and other acids and (in Section IV.C) in the reactions of substituted benzoic acids with diazodiphenylmethane (DDM). Only in the case of the latter system can really satisfactory correlation analysis be taken as the basis for discussion. For most of the other systems discussion will have to be qualitative or, at best, semi-quantitative.

B. Ionization of Carboxylic and Other Acids

Ortho-substituted benzoic acids involving electron-attracting substituents tend to be considerably stronger than their para isomers. The pKa values (water, 25 °C) for some p-X, o-X pairs are respectively as follows: NO2, 3.44, 2.17; Cl, 3.98, 2.92; F, 4.14, 3.27; SO2Me, 3.53, 2.53137; COOMe, 3.75125, 3.32 (30 °C). Thus a decrease in pKa of about one unit is typical for the effect of moving such a substituent from a para- to ortho-position. Doubtless this is considerably due to the increased inductive effect from the ortho-position. However, some contribution may also be made by the substituent twisting the carboxyl group out of the plane of the benzene ring, thereby reducing the extent of conjugation of the ring with the side-chain. This has the result of destabilizing