Alkylation addition

The introduction of additional alkyl groups mostly involves the formation of a bond between a carbanion and a carbon attached to a suitable leaving group. S,.,2-reactions prevail, although radical mechanisms are also possible, especially if organometallic compounds are involved. Since many carbanions and radicals are easily oxidized by oxygen, working under inert gas is advised, until it has been shown for each specific reaction that air has no harmful effect on yields. 

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... 

One of the most important and general trends in organic chemistry is the increase in carbocation stability with additional alkyl substitution. This stability relationship is fundamental to imderstanding many aspects of reactivity, especially of nucleophilic... 

Nitroalkanes show a related relationship between kinetic acidity and thermodynamic acidity. Additional alkyl substituents on nitromethane retard the rate of proton removal although the equilibrium is more favorable for the more highly substituted derivatives. The alkyl groups have a strong stabilizing effect on the nitronate ion, but unfavorable steric effects are dominant at the transition state for proton removal. As a result, kinetic and thermodynamic acidity show opposite responses to alkyl substitution. 

The stereoselectivity of alkylation of 3-acetylbutyrolactone is influenced by additional alkyl substituents on the ring at C-4 and C-5. Analyze possible conformations of the enolate and develop an explanation of the stereoselectivity. 

When this stereoelectronic requirement is combined with a calculation of the steric and angle strain imposed on the transition state, as determined by MM-type calculations, preferences for the exo versus endo modes of cyclization are predicted to be as summarized in Table 12.3. The observed results show the expected qualitative trend. The observed preferences for ring formation are 5 > 6, 6 > 7, and 8 > 7, in agreement with the calculated preferences. The relationship only holds for terminal double bonds. An additional alkyl substituent at either end of the double bond reduces the relative reactivity as a result of a steric effect. 

Inclusion of additional alkyl groups on the aromatic ring leads to decongestants with longer duration of action. Thus, reaction of the arylacetonitrile, 109, obtainable from hydrocarbon, 107, by chloromethylation (108), followed by displacement of the halogen by means of cyanide ion with ethylenediamine, leads to xylometazoline (111). The analogous reaction of the oxygenated derivative, 110, affords oxymetazoline (112). ... 

In situ thiol oxidation can also be done just after the tetraethoxysilane hydrolysis. Both MPTMS and H2O2 are added simultaneously before aging. This was demonstrated by Stucky et al. [69] on SBA-15 containing ffS03 and additional alkyl groups, followed by Mbaraka et al. [63], and Yang et al. [70], the latter including template removal. In situ oxidation avoids residual unreacted thiols, typically observed by postsynthetic routes. 

Several examples of tandem conjugate addition-alkylation follow. 

Tandem conjugate addition-alkylation has proven to be an efficient means of introducing groups at both a- and (3-positions at enones.307 As with simple conjugate addition, organocopper reagents are particularly important in this application, and they are discussed further in Section 8.1.2.3. 

Scheme 8.3. Tandem Conjugate Addition-Alkylation Using Organocopper Reagents... 

These facts are perfectly matched with our above-mentioned desired requirements. In addition, alkyl zinc is known to be less basic and deprotonation of ketone-aniline 36 by zinc reagent is highly unlikely. However, one of the issues for this reaction was the requirement for two alkyl groups on the zinc metal since the product ends up as tetramer 61, where the zinc atom still has one alkyl group, recalling that our cyclopropylacetylene (37) is not easy to obtain. 

The methylimidazolide reacts more slowly with an alcohol (cf. c-QHnOH) but not with respect to an amine (cf. C-QH11NH2) in comparison with the unsubstituted imi-dazolide. Introduction of an additional alkyl group into the imidazole ring further retards the transphosphorylation. Thus, the 2-ethyl-4-methylimidazolide did not react with cyclohexanol within 70 h at room temperature, while with cyclohexylamine an amide was produced, albeit with a reduction in yield.[190] Hence, a certain degree of selectivity towards amines was achieved with the 2-ethyl-4-methylimidazolide. Selectivity toward amines and alcohols was also observed with the 2-ethyl- or isopropyl-4-nitroimidazolide. 

Figure 8.B The carbon-bromine bond length (shown in angstroms) at the central carbon increases as less electron density from the bromine is needed to stabilize the positive charge. A lesser electron density contribution from bromine is needed because additional alkyl groups help stabilize the charge...

Allyl sulphones can be converted to dienes by alkylation and elimination of sulphinic acid under basic conditions (equation 64)105. Several vitamin A related polyenes have been synthesized following this two-step protocol (Table 10)106. The poor leaving-group ability of the arylsulphonyl group requires treatment with strong base for elimination. However, elimination of the allylsulphonyl group takes place readily under palladium catalysis (equation 65)107. Vinyl sulphones can be converted to dienes via Michael addition, alkylation with allyl halides and elimination of sulphinic acid sequence (equation 66)108. 

Scheme 3.6. Diastereoselectivity in silylcuprate conjugate addition-alkylation (alkyl halides) or protonation reactions with a,/S-enoates [46],...

Tandem conjugate addition-alkylation has proven to be an efficient means of introducing both a and substituents at enones."... 

Prior to protonolysis, the products of conjugate addition to unsaturated carbonyl compounds are enolates and, therefore, potential nucleophiles. A useful extension of the conjugate addition method is to combine it with an alkylation step that adds a substituent at the a position.52 Several examples of this tandem conjugate addition/alkylation procedure are given in Scheme 8.2. 

One drawback of both these methods is that only a few trialkylorthoformates are commercially available, and this limits the type of ether that can be formed. In addition, alkyl ethers are somewhat inert and not readily amenable to further synthetic manipulation. In contrast, a wide variety of alkoxytrimethylsilanes are commercially available and this fact prompted an investigation into their use [107]. 

The diquinone 300 has been shown to react with a variety of primary amines producing carbazole quinones 301, a process which presumably involves an intermediate such as 302 formed by Michael-type addition. Alkyl-, aryl-, and heteroarylamines and amino acids have been utilized. The reaction failed with p-nitro- and p-acetylanilines neutral and acidic amino acids required base catalysis. Hydroxyl-... 

Doe P, El-Emary M, Wade WH, Schechter RS (1977) Surfactants for producing low interfacial tension II. Linear alkylbenzene sulfonates with additional alkyl groups. J Am Oil Chem Soc 54 570... 

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