Substituents alkyl

The red shift of the HCl stretch, listed in the last row of Table 3.28, is considerably larger than in H O HCl. Nonetheless, this shift of 170 cm is only about half of the experimental quantity of 316 cm. The same trends are observed in. solid matrix. When the proton acceptor in the H20---HC1 complex is changed to dimethyl (or diethyl) ether, the red shift of the HCl stretch increases by several hundred cm Similarly increased red shifts vv hen the base is alkylated are noted for HF and HBr as proton donors. The sulfur analogs, namely, H2S, Mc2S, and 128, obey similar patterns when paired with HF, HCl, and HBr .  

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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. 

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.). 

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). 

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. 

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. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

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

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). 

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. 

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

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). 

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. 

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... 

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... 

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... 

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

Degree of substitution (alkyl substituents stabilize a double bond)... 

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... 

In general alkyl substituents increase the reactivity of a double bond toward elec trophilic addition Alkyl groups are electron releasing and the more electron rich a dou ble bond the better it can share its tt electrons with an electrophile Along with the observed regioselectivity of addition this supports the idea that carbocation formation rather than carbocation capture is rate determining... 

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... 

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... 

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... 

Instead of stabilizing the carbonyl group by electron donation as alkyl substituents do trifluoromethyl groups destabilize it by withdrawing electrons A less stabilized carbonyl group IS associated with a greater equilibrium constant for addition... 

Alkyl substituents have a negligible effect on acidity ... 

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

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... 

The outer layer or cortex of the adrenal gland is the source of a large group of sub stances known as corticosteroids Like the bile acids they are derived from cholesterol by oxidation with cleavage of a portion of the alkyl substituent on the D ring Cortisol IS the most abundant of the corticosteroids but cortisone is probably the best known Cortisone is commonly prescribed as an antiinflammatory drug especially m the treat ment of rheumatoid arthritis... 

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

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