The Hammett constant s

The distribution of electrons within a molecule depends on the nature of the electron withdrawing and donating groups found in that structure. For example, benzoic acid is weakly ionised in water:

Substitution of a ring hydrogen by an electron withdrawing substituent (X), such as a nitro group, will weaken the O-H bond of the carboxyl group and stabilise the carboxylate anion (Fig. 3.11). This will move the equilibrium to the right which means that the substituted compound is a stronger acid than benzoic acid (KX > K). It also means that at equilibrium more of the nitrobenzoic acid will exist as anions, which could make its transfer through membranes more difficult than that of the weaker lessionised benzoic acid. Conversely, the introduction of an electron donor substituent (X) such as a methyl group into the ring strengthens the acidic O-H group and reduces the stability of the carboxylate anion. This

COOH

COOH

Electron donor

Position of equilibrium moves to the right COOH — X^Vc substituents \=/ _ \ — / [ArCOOH]

Position of equilibrium moves to the left

Figure 3.11 The effect of electron withdrawing and donor groups on the position of equilibrium of substituted benzoic acids moves the equilibrium to the left, which means that the compound is a weaker acid than benzoic acid (K > KX). This in turn means that it has fewer anions in solution at equilibrium than benzoic acid and so could pass through membranes more easily than benzoic acid. In addition to the effect that changes in the electron distribution have on transfer through membranes, they will also have an effect on the binding of these acids to a target site. These observations show that it is possible to use equilibrium constants to compare the electron distributions of structurally similar groups of compounds.

Hammett used equilibrium constants to study the relationship between the structure of aromatic acids and acid strength. In the course of this study he calculated constants, which are now known as Hammett substituent constants (sX) or simply Hammett constants, for a variety of ring substituents (X) of benzoic acid, using this acid as the comparative reference standard (Table 3.6). These constants are related to the type and extent of the electron distribution in these aromatic acids and as a result are now used as electron distribution parameters in QSAR studies.

Table 3.6 Examples of the different electronic substitution constants used in QSAR studies. Inductive substituent constants (ctj) represent the contribution the inductive effect makes to Hammett constants and can be used for aliphatic compounds. Taft substitution constants (ct*) refer to aliphatic substituents and use the 2-methyl derivative of ethanoic acid (propanoic acid) as the reference point. The Swain-Lupton constants represent the contributions due to the inductive (F) and mesomeric or resonance (R) components of Hammett constants. Reproduced with permission from H.J. Smith and H. Williams, An Introduction to the Principles of Drug Design and Action, 3rd edn, table 5.3, 1998, Harwood Academic Publishers

Table 3.6 Examples of the different electronic substitution constants used in QSAR studies. Inductive substituent constants (ctj) represent the contribution the inductive effect makes to Hammett constants and can be used for aliphatic compounds. Taft substitution constants (ct*) refer to aliphatic substituents and use the 2-methyl derivative of ethanoic acid (propanoic acid) as the reference point. The Swain-Lupton constants represent the contributions due to the inductive (F) and mesomeric or resonance (R) components of Hammett constants. Reproduced with permission from H.J. Smith and H. Williams, An Introduction to the Principles of Drug Design and Action, 3rd edn, table 5.3, 1998, Harwood Academic Publishers

Substituent

Hammett constants

Inductive constant ri

Taft constant

CT

Swain-Lupton constants

rm

rP

F

R

-H

0.00

0.00

0.00

0.49

0.00

0.00

-ch3

- 0.07

-

0.17

- 0.05

0.00

0.04 -

0.13

-C2H5

- 0.07

-

0.15

- 0.05

- 0.10

- 0.05 -

0.10

-Ph

0.06

-

0.01

0.10

0.60

0.08 -

0.08

-OH

0.12

-

0.37

0.25

-

0.29 -

0.64

-Cl

0.37

0.23

0.47

-

0.41 -

0.15

-NO2

0.71

0.78

-

-

0.67

0.16

Hammett constants (sX) are defined as:

that is:

A negative value for sX indicates that the substituent is acting as an electron donor group since K >> KX. Conversely, a positive value for sX shows that the substituent is acting as an electron withdrawing group as K < KX. The value of sX varies with the position of the substituent in the molecule. Consequently, this position is usually indicated by the use of the subscripts o, m and p. Where a substituent has opposite signs depending on its position on the ring it means that in one case it is acting as an electron donor and in the other as an electron withdrawing group. This is possible because the Hammett constant includes both the inductive and mesomeric (resonance) contributions to the electron distribution. For example, the sm Hammett constant for the methoxy group of m-methoxybenzoic acid is 0.12 whilst for p-methoxybenzoic acid it is — 0.27. In the former case the electronic distribution is dominated by the inductive (I or F) contribution whilst in the latter case it is controlled by the mesomeric (M) or resonance (R) effect (Fig. 3.12).

i m-Methoxybenzoic acid

i m-Methoxybenzoic acid

p-Methoxybenzoic acid

:och3

Figure 3.12 The inductive and mesomeric effects of m-methoxybenzoic and p-methoxybenzoic acids

:och3

Hammett postulated that the s values calculated for the ring substituents of a series of benzoic acids could also be valid for those ring substituents in a different series of similar aromatic compounds. This relationship has been found to be in good agreement for the meta and para substituents of a wide variety of aromatic compounds but not for their ortho substituents. The latter is believed to be due to steric hindrance and other effects, such as intramolecular hydrogen bonding, playing a significant part in the ionisations of compounds with ortho substituents. Hammett substitution constants also suffer from the disadvantage that they only apply to substituents directly attached to a benzene ring. Consequently, a number of other electronic constants (Table 3.6) have been introduced and used in QSAR studies in a similar manner to the Hammett constants. However, Hammett substitution constants are probably still one of the most widely used electronic parameters for QSAR studies.

Attempts to relate biological activity to the values of Hammett substitution and similar constants have been largely unsuccessful since electron distribution is not the only factor involved (see section 3.7). However, a successful attempt to relate biological activity to structure using Hammett constants was the investigation by Fukata and Metcalf into the effectiveness of diethyl aryl phosphates for killing fruit flies. This investigation showed that the activity of these compounds is dependent only on electron distribution factors. Their results may be expressed by the relationship:

OC2H5

Diethyl aryl phosphate insecticides O— P—O—^

OC2H5

This equation shows that the greater the positive value for s, the greater the biological activity of the analogue. This type of knowledge enables one to predict the activities of analogues and synthesise the most promising rather than spend a considerable amount of time synthesising and testing all the possible analogues.

Was this article helpful?

0 0
Insider Nutrition Secrets

Insider Nutrition Secrets

Secrets To Living Longer And Healthier Revealed By Nutrition Scientist! Insider Nutrition Secrets. Have you ever wondered what it might be like to find the long lost Fountain of Youth? We cant promise you that, but we can give you a close second. Starting today, learn the facts about what your body really needs to survive longer and healthier. Discover insider information from a former food and drug expert. Learn how a new food or drug is developed from the beginning until it finally reaches your grocers shelves.

Get My Free Ebook


Post a comment