Substituent effects alkyl groups

A mechanism has been proposed to rationalize the results shown in Figure 23. The relative proportion of the A -pyrazolines obtained by the reduction of pyrazolium salts depends on steric and electronic effects. When all the substituents are alkyl groups, the hydride ion attacks the less hindered carbon atom for example when = Bu only C-5 is attacked. The smaller deuterohydride ion is less sensitive to steric effects and consequently the reaction is less selective (73BSF288). Phenyl substituents, both on the nitrogen atom and on the carbon atoms, direct the hydride attack selectively to one carbon atom and the isolated A -pyrazoline has the C—C double bond conjugated with the phenyl (328 R or R = Ph). Open-chain compounds are always formed during the reduction of pyrazolium salts, becoming predominant in the reduction of amino substituted pyrazoliums. 

A frequently encountered problem in chemistry concerns the effect of a substituent on the properties of a parent molecule. Perhaps the most important, and certainly the most studied (.6), class of substituents are alkyl groups. The highest-lying occupied TV orbitals of molecules such as ethylene, formaldehyde, and benzene are well known to be destabilized by alkyl substitution. The situation for the n orbitals is much less clear. From our ETS studies (4, T, 8) we have found that alkyl substitution destabilizes the LUMO of ethylene and formaldehyde but slightly stabilizes that of benzene, toluene, and t-butylbenzene. This result is particularly significant because the conventional picture of resonance and inductive effects leads one to expect that alkyl substitution should also destabilize the benzene tv orbitals Csee Figure 1). 

In recent years a large number of jS-keto esters, and some /5-diketones have been investigated in an attempt to discover some of the smaller effects of the substituents, especially alkyl groups on the keto-enol equilibrium. In Table 34 are given the values for the equilibrium constant... 

Experimental measurements of dipole moments give size but not direction We normally deduce the overall direction by examining the directions of individual bond dipoles With alkenes the basic question concerns the alkyl groups attached to C=C Does an alkyl group donate electrons to or withdraw electrons from a double bond d This question can be approached by comparing the effect of an alkyl group methyl for exam pie with other substituents... 

Table 6 3 shows that the effect of substituents on the rate of addition of bromine to alkenes is substantial and consistent with a rate determining step m which electrons flow from the alkene to the halogen Alkyl groups on the carbon-carbon double bond release electrons stabilize the transition state for bromonium ion formation and increase the reaction rate... 

Consider first the electronic effect of alkyl groups versus hydrogen atoms attached to C=0 Recall from Section 17 2 that alkyl substituents stabilize C=0 making a ketone carbonyl more stable than an aldehyde carbonyl As with all equilibria factors... 

Acylation. Acylation is the most rehable means of introducing a 3-substituent on the indole ring. Because 3-acyl substituents can be easily reduced to 3-aLkyl groups, a two-step acylation—reduction sequence is often an attractive alternative to direct 3-aLkylation. Several kinds of conditions have been employed for acylation. Very reactive acyl haUdes, such as oxalyl chloride, can effect substitution directiy without any catalyst. Normal acid chlorides are usually allowed to react with the magnesium (15) or 2inc (16) salts. The Vilsmeier-Haack conditions involving an amide and phosphoms oxychloride, in which a chloroiminium ion is the active electrophile, frequentiy give excellent yields of 3-acylindoles. 

Steric and inductive effects determine the rate of formation of the pentacovalent siUcon reaction complex. In alkaline hydrolysis, replacement of a hydrogen by alkyl groups, which have lower electronegativity and greater steric requirements, leads to slower hydrolysis rates. Replacement of alkyl groups with bulkier alkyl substituents has the same effect. Reaction rates decrease according to ... 

Whereas introducing a thiol moiety at C-7 markedly reduced the antibacterial activity relative to lincomycin (79), the 7(3)-7-deoxy-7-alkylthiolincomycins exhibited considerably enhanced antibacterial activity without apparent regard for the size of the alkyl group (80—82). A marked increase in gram-negative activity was shown when the 7(3)-substituent contained a 2- or 3-hydroxy or amino group, but this activity was insufficient to be effective in infected mice (83—85). 

Substituents with -I,+M effects such as halogen show a similar orientation effect to that of alkyl groups. If the substituent is in the 2-position, substitution occurs at C-5 if it is in position 3, substitution occurs preferentially at C-2 or if steric requirements of the group or electrophile intervene, then substitution occurs at C-5. 

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