Leaving groups amination reactions

We can explain the observed pH dependence of imine formation by looking at the individual steps in the mechanism. As indicated in Figure 19.8, an acid catalyst is required in step 3 to protonate the intermediate carbinolamine, thereby converting the —OH into a better leaving group. Thus, reaction will be slow if not enough acid is present (that is, at high pH). On the other hand, if too much acid is present (low pH), the basic amine nucleophile is completely protonated, so the initial nucleophilic addition step can t occur. 

Step 1 of Figure 29.14 Transimination The first step in transamination is trans-imination—the reaction of the PLP—enzyme imine with an a-amino acid to give a PLP—amino acid imine plus expelled enzyme as the leaving group. The reaction occurs by nucleophilic addition of the amino acid -NH2 group to the C=N bond of the PLP imine, much as an amine adds to the C=0 bond of a ketone or aldehyde in a nucleophilic addition reaction (Section 19.8). The pro-tonated diamine intermediate undergoes a proton transfer and expels the lysine amino group in the enzyme to complete the step. 

Azetidines are often synthesized by reacting 1,3-dihalogenopropanes with an amine (ammonia gives poor yields), or from propane-1,3-diamines where one A-substituent can function as a leaving group. A reaction of the latter type is used to synthesize azetidine from A,A-bis(toluenesul-fonyl)-l,3-diaminopropane in two steps, the last being a reductive A-de-toluenesulfonation, caused by adding sodium to naphthalene in an inert solvent (Scheme 8.5). 

Although the formation of secondary amines by way of Mannich reactions is much less well documented than is the case for the formation of tertiary amines, two other methods have been reported which provide access to secondary amines. In addition to the use of benzotriazole in reactions leading to the formation of tertiary amines, it has also been used as an efficient leaving group in reactions leading to the formation of secondary amines <9274971), as shown in Equation... 

A quaternary ammonium ion can undergo an elimination reaction with a strong base such as hydroxide ion. The reaction is known as a Hofinann elimination reaction. The leaving group in a Hofmann elimination reaction is a tertiary amine. Because a tertiary amine is a relatively poor leaving group, the reaction requires heat. 

Imidazole can be A -allylated. The A -glycosylimidazole 299 is prepared by regiospecific amination at the anomeric center with retention of configuration. Phenoxy is a good leaving group in this reaction[181]. Heterocyclic amines such as the purine base 300 are easily allylatedfl 82]. 

The product of this series of steps is an alkyl diazonium ion, and the amine is said to have been diazotized Alkyl diazonium ions are not very stable decomposing rapidly under the conditions of their formation Molecular nitrogen is a leaving group par excel lence and the reaction products arise by solvolysis of the diazonium ion Usually a car bocation intermediate is involved... 

The perhydrolysis reaction could theoretically continue to give four moles of peracid per mole of TAED but stops at this stoichiometry because of the substantial increase in the conjugate acid pify of the leaving group going from an amide (p-R = 17) to an amine (pif = 35) (94,95). Nonanoyloxybenzene sulfonate (NOBS) [101482-85-3] is used in detergent products in the United States and Japan. The NOBS perhydrolysis reaction is shown in equation 20 (96). 

Methyl bromide slowly hydrolyzes in water, forming methanol and hydrobromic acid. The bromine atom of methyl bromide is an excellent leaving group in nucleophilic substitution reactions and is displaced by a variety of nucleophiles. Thus methyl bromide is useful in a variety of methylation reactions, such as the syntheses of ethers, sulfides, esters, and amines. Tertiary amines are methylated by methyl bromide to form quaternary ammonium bromides, some of which are active as microbicides. 

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

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