Substituent space

QSAR models can be a valuable means of predicting the toxicity of untested nonelectrolyte organic chemicals. The models need to be derived from a series of chemicals acting by a common molecular mechanism and encompass an adequate domain of spanned substituent space in their physical and chemical properties. The acute toxicity of many classes of nonelectrolytes is consistent with a narcosis or baseline toxicity mechanism. The ability to apply such models for predictive purposes also requires information to suggest that the candidate chemical acts by the same mechanism. 

FIGURES Comparison of spanned substituent space for 17 alkyl- and chloroanilines employed by Mermens et al. (above), and anilines in this study (below). 

B. If the seed atom has two neighbors, no triple bonds, and no more than two double bonds, make it pseudotrigonal change the substituent spacing to 120° (not the prevailing chain angle). 

Nuclear Overhauser enhancement (NOE) spectroscopy has been used to measure the through-space interaction between protons at and the protons associated with the substituents at N (20). The method is also useful for distinguishing between isomers with different groups at and C. Reference 21 contains the chemical shifts and coupling constants of a considerable number of pyrazoles with substituents at N and C. NOE difference spectroscopy ( H) has been employed to differentiate between the two regioisomers [153076 5-0] (14) and [153076 6-1] (15) (22). N-nmr spectroscopy also has some utility in the field of pyrazoles and derivatives. 

It is often necessary to prepare /3-lactams with particular substituents at N-1, C-3 and C-4, e.g. in the preparation of fused /3-lactams from monocyclic precursors. For reasons of space it is not possible to give an exhaustive list of the variously substituted /3-lactams available however, Table 4 summarizes the most general routes to /3-lactams bearing particular substituents at C-3 and C-4. -Substitution of azetidin-2-ones has already been dealt with cf. Section 5.09.3.2.3). N-Unsubstituted /3-lactams and protected 3-amino-/3-lactams are particularly important synthetic intermediates and methods of preparing these are discussed below. 

Figure 5.24 Space-filling model (green) of the sialic acid binding domain of hemagglutinin with a bound inhibitor (red) Illustrating the different binding grooves. The sialic acid moiety of the Inhibitor binds in the central groove. A large hydrophobic substituent, Ri, at the Cz position of sialic acid binds in a hydrophobic channel that runs from the central groove to the bottom of the domain. (Adapted from S.J. Watowich et al.. Structure 2 719-731, 1994.)...

The ortho effect may consist of several components. The normal electronic effect may receive contributions from inductive and resonance factors, just as with tneta and para substituents. There may also be a proximity or field electronic effect that operates directly between the substituent and the reaction site. In addition there may exist a true steric effect, as a result of the space-filling nature of the substituent (itself ultimately an electronic effect). Finally it is possible that non-covalent interactions, such as hydrogen bonding or charge transfer, may take place. The role of the solvent in both the initial state and the transition state may be different in the presence of ortho substitution. Many attempts have been made to separate these several effects. For example. Farthing and Nam defined an ortho substituent constant in the usual way by = log (K/K ) for the ionization of benzoic acids, postulating that includes both electronic and steric components. They assumed that the electronic portion of the ortho effect is identical to the para effect, writing CTe = o-p, and that the steric component is equal to the difference between the total effect and the electronic effect, or cts = cr — cte- They then used a multiple LFER to correlate data for orrAo-substituted reactants. 

This illustrates an important distinction in chemical enumeration that between the enumeration of "structural" isomers, in which only the connections between the atoms are considered, and that of stereoisomers, in which the situation of a molecule in space is important, so that as above we can have right- and left-hand forms of a molecule. This distinction will occur, for example, when a carbon atom is bonded to four distinct substituents (it can occur in many other ways). Such a carbon atom is said to be asymmetrical. 

If we disallow reflections, thus heeding the fact that the molecule exists in three-dimensional space, we must use the alternating group instead of S. In this case, as the reader can verify, the total number of configurations becomes 36. This shows that in the latter case there are two distinct configurations which become equivalent if reflection is allowed these are precisely the two configurations in which the substituents are all different. 

Ethylene is not unique in its ability to form a polymer. Many substituted ethyl-enes, called vinyl monomers, also undergo polymerization to yield polymers with substituent groups regularly spaced on alternating carbon atoms along the chain. Propylene, for example, yields polypropylene, and styrene yields polystyrene. 

As suggested by Roberts and Moreland many years ago (1953), the acidity constants of 4-substituted bicyclooctane-l-carboxylic acids provide a very suitable system for defining a field/induction parameter. In this rigid system the substituent X is held firmly in place and there is little possibility for mesomeric delocalization or polarization interactions between X and COOH (or COO-). Therefore, it can be assumed that X influences the deprotonation of COOH only through space (the field effect) and through intervening o-bonds. On this basis Taft (1956, p. 595) and Swain and Lupton (1968) were able to calculate values for o and crR. 

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