Substituents alkyl

Alkyl substituents stabilize a carbonyl group m much the same way that they sta bilize carbon-carbon double bonds and carbocations—by releasing electrons to sp hybridized carbon Thus as then heats of combustion reveal the ketone 2 butanone is more stable than its aldehyde isomer butanal 

Alkyl substituents have a negligible effect on acidity  

The steric effects of alkyl substituents (R= methyl, ethyl, i-propyl, f-butyl) on the nitrogen have been related to the steric factors of these same groups as measured in kinetic studies (152). 

When the carbon chain bears both a halogen and an alkyl substituent the two are con sidered of equal rank and the chain is numbered so as to give the lower number to the substituent nearer the end of the chain 

C=C—H 3340-3270 (w-m) Alkyl substituents at higher frequencies unsaturated or aryl substituents at lower frequencies 

Degree of substitution (alkyl substituents stabilize a double bond) 

Chapter 12. Modification of 3-Alkyl Substituents by Nucleophilic Substitution. 119 

Carbocations are stabilized by alkyl substituents attached directly to the positively charged carbon Alkyl groups are electron releasing sub stituents Stability increases in the order 

Alkenes are relatively nonpolar Alkyl substituents donate electrons to an sp hybridized carbon to which they are attached slightly better than hydrogen does 

Section 5 6 Electron release from alkyl substituents stabilizes a double bond In gen eral the order of alkene stability is 

Some of the evidence indicating that alkyl substituents stabilize free radicals comes from bond energies The strength of a bond is measured by the energy required to break It A covalent bond can be broken m two ways In a homolytic cleavage a bond between two atoms is broken so that each of them retains one of the electrons m the bond 

For 4-nitro-5-alkylthiazoles, the prefered conformations of the alkyl substituents relative to the ir-system could be evaluated, and the interactions between alkyl and nitro groups were demonstrated to be negligible. 

Dialkylation of ethyl acetoacetate can also be accomplished opening the way to ketones with two alkyl substituents at the a carbon 

Like carbocations free radicals are stabilized by alkyl substituents The order of free radical stability parallels that of carbocation stability 

Ethane tetracarboxylic ethyl ester can be regarded as composed of two malonic ester residues, each acting as a mono-alkyl substituent to the other. The two remaining hydrogen atoms therefore still retain acidic properties, and consequently the ester gives with sodium ethoxide a di-sodium derivative. 

As is broadly true for aromatic compounds, the a- or benzylic position of alkyl substituents exhibits special reactivity. This includes susceptibility to radical reactions, because of the. stabilization provided the radical intermediates. In indole derivatives, the reactivity of a-substituents towards nucleophilic substitution is greatly enhanced by participation of the indole nitrogen. This effect is strongest at C3, but is also present at C2 and to some extent in the carbocyclic ring. The effect is enhanced by N-deprotonation. 

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 

In readily available (see p. 22f.) cyclic imidoesters (e.g. 2-oxazolines) the ot-carbon atom, is metallated by LDA or butyllithium. The heterocycle may be regarded as a masked formyl or carboxyl group (see p. 22f.), and the alkyl substituent represents the carbon chain. The lithium ion is mainly localized on the nitrogen. Suitable chiral oxazolines form chiral chelates with the lithium ion, which are stable at —78°C (A.I. Meyers, 1976 see p. 22f.). 

These preceding properties imply that the thiazole has to be introduced in various molecules, by direct cyclization or with precursors already bearing the thiazole ring. Among these last products the clomethiazole. nitrothiazole, and aryl or alkylthiazoles with the functional group on the aryl or alkyl substituent have been widely used. 

TrialkyIboranes (p. 9), which can be synthesized from olefins and diborane, undergo alkyl coupling on oxidation with alkaline silver nitrate via short-lived silver organyls. Two out of three alkyl substituents are coupled in this reaction. Terminal olefins may be coupled by this reaction sequence in 40 - 80% yield. With non-terminal olefins yields drop to 30 - 50% (H.C. Brown, 1972C, 1975). 

Auto-association of A-4-thiazoline-2-thione and 4-alkyl derivatives has been deduced from infrared spectra of diluted solutions in carbon tetrachloride (58. 77). Results are interpretated (77) in terms of an equilibrium between monomer and cyclic dimer. The association constants are strongly dependent on the electronic and steric effects of the alkyl substituents in the 4- and 5-positions, respectively. This behavior is well shown if one compares the results for the unsubstituted compound (K - 1200 M" ,). 4-methyl-A-4-thiazoline-2-thione K = 2200 M ). and 5-methyl-4-r-butyl-A-4-thiazoline-2-thione K=120 M ) (58). 

Aryl halides react too slowly to undergo substitution by the Sn2 mechanism with the sodium salt of diethyl malonate and so the phenyl substituent of phenobarbital cannot be introduced in the way that alkyl substituents can 

Retrosynthetic path b in Scheme 3.1 corresponds to reversal of the electrophilic and nucleophilic components with respect to the Madelung synthesis and identifies o-acyl-iV-alkylanilines as potential indole precursors. The known examples require an aryl or EW group on the iV-alkyl substituent and these substituents are presumably required to facilitate deprotonation in the condensation. The preparation of these starting materials usually involves iV-alkyla-tion of an o-acylaniline. Table 3.3 gives some examples of this synthesis. 

We have seen this situation before m the reaction of alcohols with hydrogen halides (8ection 4 11) m the acid catalyzed dehydration of alcohols (8ection 5 12) and m the conversion of alkyl halides to alkenes by the El mechanism (8ection 5 17) As m these other reactions an electronic effect specifically the stabilization of the carbocation intermediate by alkyl substituents is the decisive factor The more stable the carbo cation the faster it is formed 

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