Nucleophiles special

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

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. 

Thiazolium derivatives unsubstituted at the 2-position (35) are potentially interesting precursors of A-4-thiazoline-2-thiones and A-4-thiazoline-2-ones. Compound 35 in basic medium undergoes proton abstraction leading to the very active nucleophilic species 36a and 36b (Scheme 16) (43-46). Special interest has been focused upon the reactivity of 36a and 36b because they are considered as the reactive species of the thiamine action in some biochemical reaction, and as catalysts for several condensation reactions (47-50). 

As crowding at the carbon that bears the leaving group decreases the rate of nude ophilic attack by the Lewis base increases A low level of steric hindrance to approach of the nucleophile is one of the special circumstances that permit substitution to pre dominate and primary alkyl halides react with alkoxide bases by an 8 2 mechanism m preference to E2... 

When we say cycloheptatriene is not aromatic but cycloheptatrienyl cation is we are not comparing the stability of the two to each other Cycloheptatriene is a stable hydrocarbon but does not possess the special stability required to be called aromatic Cycloheptatrienyl cation although aromatic is still a carbocation and reasonably reac tive toward nucleophiles Its special stability does not imply a rock like passivity but rather a much greater ease of formation than expected on the basis of the Lewis struc ture drawn for it A number of observations indicate that cycloheptatrienyl cation is far more stable than most other carbocations To emphasize its aromatic nature chemists often write the structure of cycloheptatrienyl cation m the Robinson circle m a ring style... 

The most common types of aryl halides m nucleophilic aromatic substitutions are those that bear o ox p nitro substituents Among other classes of reactive aryl halides a few merit special consideration One class includes highly fluormated aromatic compounds such as hexafluorobenzene which undergoes substitution of one of its fluorines on reac tion with nucleophiles such as sodium methoxide... 

Chemical Properties. The chemistry of ketenes is dominated by the strongly electrophilic j/)-hybridi2ed carbon atom and alow energy lowest unoccupied molecular orbital (LUMO). Therefore, ketenes are especially prone to nucleophilic attack at Cl and to [2 + 2] cycloadditions. Less frequent reactions are the so-called ketene iasertion, a special case of addition to substances with strongly polarized or polarizable single bonds (37), and the addition of electrophiles at C2. For a review of addition reactions of ketenes see Reference 8. 

Etherification. The accessible, available hydroxyl groups on the 2, 3, and 6 positions of the anhydroglucose residue are quite reactive (40) and provide sites for much of the current modification of cotton ceUulose to impart special or value-added properties. The two most common classes into which modifications fall include etherification and esterification of the cotton ceUulose hydroxyls as weU as addition reactions with certain unsaturated compounds to produce ceUulose ethers (see Cellulose, ethers). One large class of ceUulose-reactive dyestuffs in commercial use attaches to the ceUulose through an alkaH-catalyzed etherification by nucleophilic attack of the chlorotriazine moiety of the dyestuff ... 

Isoxazolium salts can be prepared by reaction with alkyl iodides or sulfates, although the low basicity of isoxazoles and their sensitivity to nucleophilic attack may necessitate special care. Isoxazolium salts containing bulky Af-substituents can be prepared by the reaction of isoxazoles with alcohols in the presence of perchloric acid. For example, the reaction of 3,5-dimethylisoxazole (53) with some alcohols in the presence of 70% perchloric acid gave isoxazolium salts, (54a) in 29%, (54b) in 57% and (54c) in 82% yield 79AHC(25)147, 68JOC2397). Attempts to quaternize 3,5-dimethyl-4-nitroisoxazole failed 71JCS(B)2365). 

Examples of effects of reactant stmcture on the rate of nucleophilic substitution reactions have appeared in the preceding sections of this chapter. The general trends of reactivity of primaiy, secondary, and tertiaiy systems and the special reactivity of allylic and benzylic systems have been discussed in other contexts. This section will emphasize the role that steric effects can pl in nucleophilic substitution reactions. 

Hydrolysis of aspirin in H2 0 leads to no incorporation of into the product salicylic acid, ruling out the anhydride as an intermediate and thereby excluding mechanism 1. The general acid catalysis of mechanism III can be ruled out on the basis of failure of other nucleophiles to show evidence for general acid catalysis by the neighboring carboxylic acid group. Because there is no reason to believe hydroxide should be special in this way, mechanism III is eliminated. Thus, mechanism II, general base catalysis of hydroxide-ion attack, is believed to be the correct description of the hydrolysis of aspirin. 

The existence of n-complex intermediates can be inferred from experiments in which they are trapped by nucleophiles under special circumstances. For example, treatment of the acid 1 with bromine gives the cyclohexadienyl lactone 2. This product results from capture of the n-complex by intramolecular nucleophilic attack by the carboxylate group ... 

These reactions do not appear to involve free carbocations, because they proceed effectively in nucleophilic solvents that would successfully compete with halide or similar anions for free carbocations. Also, rearrangements are unusual under these conditions, although they have been observed in special cases. 

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

The relations in Scheme V take into account intranuclear and intemuclear resonance activation and the special cases of 2-Le-3-aza (poor) and 4-Le-8-aza (extremely poor) activation as well as the two groups of inductive activation the possibility of an accelerative peri effect in substitutions with protic nucleophiles is indicated by the sign for 4-Le-5-aza compounds. 

Reactions between A -(l-chloroalkyl)pyridinium chlorides 33 and amino acids in organic solvents have a low synthetic value because of the low solubility of the amine partner. A special protocol has been designed and tested in order to circumvent this drawback. Soon after the preparation of the salt, an aqueous solution of the amino acid was introduced in the reaction medium and the two-phase system obtained was heated under reflux for several hours. However, this was not too successful because sulfur dioxide, evolved during the preparation of the salt, was converted into sulfite that acted as an 5-nucleophile. As a result, A -(l-sulfonatoalkyl)pyridinium betaines such as 53 were obtained (Section IV,B,3) (97BSB383). To avoid the formation of such betaines, the salts 33 were isolated and reacted with an aqueous solution of L-cysteine (80) to afford thiazolidine-4-carboxylic acids hydrochlorides 81 (60-80% yields). 

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