Alkyl halides using bulky base

When a synthesis must begin with a primary alkyl halide, use a bulky base. 

When a synthesis must b in with a primary alkyl halide, use a bulky base. Why Because the steric bulk of the base will inhibit substimtion. 

Secondary alkyl halides can undergo both SN2 and E2 reactions to give a mixture of products. However, the substitution product predominates if a polar aprotic solvent is used and the nucleophile is a weak base. Elimination will predominate if a strong base is used as the nucleophile in a polar, protic solvent. In this case, bulky bases are not so crucial and the use of ethoxide in ethanol will give more elimination product than substitution product. Increasing the temperature of the reaction favours E2 elimination over Sn2 substitution as explained above. 

Chemoselective E2 eliminations can be carried out with sterically hindered, sufficiently strong bases. Their bulkiness causes them to react with an H atom at the periphery of the molecule rather than at a C atom deep within the molecule. These bases are therefore called nonnucleo-philic bases. The weaker nonnucleophilic bases include the bicyclic amidines DBN (diazabi-cyclononene) and DBU (diazabicycloundecene). These can be used to carry out chemoselective E2 eliminations even starting from primary and secondary alkyl halides and sulfonates (Figure 4.17). 

The dehydrohalogenation of bromocyclohexane illustrates the use of a bulky base for elimination. Bromocyclohexane, a secondary alkyl halide, can undergo both substitution and elimination. Elimination (E2) is favored over substitution (Sn2) by using a bulky base such as diisopropylamine. Diisopropylamine is too bulky to be a good nucleophile, but it acts as a strong base to abstract a proton. 

Typical bases such as sodium hydroxide or an alkoxide ion cannot be used to form enolates for alkylation because at equilibrium a large quantity of the hydroxide or alkoxide base is still present. These strongly nucleophilic bases give side reactions with the alkyl halide or tosylate. Problem 22-4 shows an example of these side reactions. Lithium diisopropylamide (LDA) avoids these side reactions. Because it is a much stronger base, LDA converts the ketone entirely to its enolate. All the LDA is consumed in forming the enolate, leaving the enolate to react without interference from the LDA. Also, LDA is a very bulky base and thus a poor nucleophile, so it generally does not react with the alkyl halide or tosylate. 

A secondary alkyl halide can form both substitution and elimination products under Sn2/E2 conditions. The relative amounts of the two products depend on the base strength and the bulk of the nucleophile/base. The stronger and bulkier the base, the greater the percentage of the elimination product. For example, acetic acid is a stronger acid = 4.76) than ethanol (pA a = 15.9), which means that acetate ion is a weaker base than ethoxide ion. The elimination product is the main product formed from the reaction of 2-chloropropane with the strongly basic ethoxide ion, whereas no elimination product is formed with the weakly basic acetate ion. The percentage of elimination product produced would be increased further if the bulky ferf-butoxide ion were used instead of ethoxide ion (Section 10.3). 

Sonogashira coupling reactions of primary alkyl halides have been reported. " The key to this was the use of an NHC ligand with bulky alkyl groups on the two nitrogen atoms (Scheme 2.121) lAd 1.51 and ItBu 1.55. This reaction is an alternative to the classical alkylation of acetylides ions with alkyl halides, with the advantage that base-sensitive functionality is tolerated. 

Size of the Base/Nucleophile Increasing the reaction temperature is one way of favorably influencing an elimination reaction of an alkyl halide. Another way is to use a strong sterically hindered base such as the tert-butoxide ion. The bulky methyl groups of the... 

DBN and DBU are bulky bases commonly used to encourage elimination over substitution. Like other amines, they are relatively strong bases even though they are neutral compounds. These compounds are so bulky that only the elimination reaction occurs with a secondary alkyl halide. 

Remember that alkyl halides can also undergo E2 and El reactions (Sections 10.1 and 10.3). Notice that a bulky base (tm-BuO ) is used to encourage elimination over substitution. 

Much of the reactivity of amido ligands involves proton exchange processes that eliminate amine. The exchange is believed to occur by an associative mechanism consequently, the rate of reaction decreases for sterically congested metal complexes. For example, treatment of V[N(CH3)2]j with terf-butanol at room temperature forms V(O-f-Bu) in good yield, while at this temperature the more encumbered complex W[N(CH3)2] reacts only slowly with methanol and ethanol, and not at all with tert-butanoV° The use of bulky N-alkyl substituents allows for the isolation of low-coordinate complexes, such as Cr[N( -Pr)2]3- Amido complexes derived from primary amines can also serve as precursors to imido complexes. In many cases, amido halide complexes form imido complexes by loss of hydrogen chloride in the presence of a base (Equation 4.17). ... 

There has been an outburst of research interest in the structures, physical properties, and chemistry of the group 2 metal aryloxides. This is particularly true for the elements strontium and barium where work has been stimulated by the possible use of metal aryloxides as precursors (either via sol-gel or MOCVD processes) for the formation of binary and ternary oxides containing these metals.2 Synthetic procedures are based on either the halide (Be) alkyl derivatives (Mg, Grignard derivatives, etc.) or the actual metallic element (Ca, Sr, Ba). Structural studies (Tables 6.14-6.18) show for the smaller elements Be, Mg, and Ca that monomeric and dimeric structural motifs dominate, with rarer examples of trinuclear clusters, e.g. [Ca3(OPh)5(HMPA)6][OPh.2HOPh].2 2 in the case of strontium and barium a more extensive cluster chemistry has been developed for small aryloxide ligands, while monomeric units with terminal aryloxides can be formed with bulky ligands and sufficient additional Lewis bases, e.g. [Ba(OC6H2Bu2-2,6-Me-4)2(THF)3].2 ... 

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