Nucleophiles Subject

A soln. of 2,6-di-ferf-butyl-p-cresol in acetonitrile containing LiC104 and water as nucleophile subjected ca. 15 min. to a constant current of 200 mA at a Pt-gauze anode with a carbon rod as cathode -> 2,6-di-rer -butyl-4-hydroxy-4-methylcyclo-hexa-2,5-dienone. Y 86%. - Similarly with methanol as nucleophile > 4-methoxy analog. Y 88% with Na-acetate in acetonitrile-acetic acid -> 4-acetoxy analog. Y 91%. F. e. s. A. Ronlan and V. D. Parker, Soc. (C) 1971, 3214. 

The ability of nucleophilic substitution to provide either 2,6-cis or 2,6-trans THP has been exploited in the synthesis of several natural products. Williams and coworkers reported the formation of both the A and B ring of leucascandrolide A by nucleophilic substitution (Scheme 14) [35]. Both examples relied oti a methanesulfonate leaving group and secondary alcohol nucleophile. Subjecting mesylate 44 (or 46) to sodium hydride deprotonation followed by heating resulted in THP product 45 (or 47) in 75 % yield as a single diastereomer. 

The mechanisms by which nucleophilic substitution takes place have been the subject of much study Extensive research by Sir Christopher Ingold and Edward D Hughes and their associates at University College London during the 1930s emphasized kinetic and stereochemical measurements to probe the mechanisms of these reactions... 

Sulfonate esters are subject to the same limitations as alkyl halides Competition from elimination needs to be considered when planning a functional group transforma tion that requires an anionic nucleophile because tosylates undergo elimination reactions just as alkyl halides do... 

The mechanism of anionic polymerization of cyclosiloxanes has been the subject of several studies (96,97). The first kinetic analysis in this area was carried out in the early 1950s (98). In the general scheme of this process, the propagation/depropagation step involves the nucleophilic attack of the silanolate anion on the sUicon, which results in the cleavage of the siloxane bond and formation of the new silanolate active center (eq. 17). 

The chemistry of this cure system has been the subject of several studies (44—47). It is now generally accepted that the cure mechanism involves dehydrofluorination adjacent to hexafluoropropylene monomer units. The subsequent fluoroolefin is highly reactive toward nucleophilic attack by a variety of curatives (eg, diamines, diphenols). 

In this section three main aspects will be considered. Firstly, the basic strengths of the principal heterocyclic systems under review and the effects of structural modification on this parameter will be discussed. For reference some pK values are collected in Table 3. Secondly, the position of protonation in these carbon-protonating systems will be considered. Thirdly, the reactivity aspects of protonation are mentioned. Protonation yields in most cases highly reactive electrophilic species. Under conditions in which both protonated and non-protonated base co-exist, polymerization frequently occurs. Further ipso protonation of substituted derivatives may induce rearrangement, and also the protonated heterocycles are found to be subject to ring-opening attack by nucleophilic reagents. 

The competitive attack at either oxygen or nitrogen by nucleophiles was the subject of a recent investigation (8IJOC6IO). Whereas triphenylphosphine reacted with oxaziridine (88)... 

Another feature of systems that are subject to B-strain is their reluctance to form strained substitution products. The cationic intermediates usually escape to elimination products in preference to capture by a nucleophile. Rearrangements are also common. 2-Methyl-2-adamantyl p-nitrobenzoate gives 82% methyleneadamantane by elimination and 18% 2-methyl-2-adamantanol by substitution in aqueous acetone. Elimination accounts for 95% of the product from 2-neopentyl-2-adaman l p-nitrobenzoate. The major product (83%) from 2-r-butyl-2-adamantyl p-nitrobenzoate is the rearranged alkene 5. 

Interpretation of tiie ratio of capture of competing nucleophiles has led to the estimate that bromonium ions have lifetimes on the order of 10 s in methanol. This lifetime is about 100 times longer than fliat for secondary caibocations. There is also direct evidence for the existence of bromonium ions. The bromonium ion related to propene can be observed by NMR spectroscopy when l-bromo-2-fluoropropane is subjected to superacid conditions. The terminal bromine adopts a bridging position in the resulting cation. 

The iminium salts are of course especially Subject to attack by nucleophiles, and reactions of this type are discussed in Chapter 5. See also Section V.H. 

In most reviews of enamine chemistry the reactions of iminium salts are scattered throughout the review and are consequently not covered in a comprehensive manner. This chapter will be an attempt to look at reactions that, at one stage or another, proceed by nucleophilic addition to the iminium intermediate. The subject of enamines has been reviewed 1-4) and certain aspects of iminium salt chemistry such as reduction of aromatic quaternary salts have been treated in detail (5). Consequently, the reduction of aromatic quaternary salts with complex hydrides will be presented here only briefly. Although the literature (especially 1950-1967) has been checked with care, the author can make no claim to completeness. The... 

The presence of iminium salts can be detected by chemical means or by spectroscopic methods. The chemical means of detecting iminium salts are reactions with nucleophiles and are the subject of this review. The spectroscopic methods are more useful for rapid identification because with the large number of model compounds available now the spectroscopic methods are fast and reliable. The two methods that are used primarily are infrared and nuclear magnetic resonance spectroscopy. Some attempts have been made to determine the presence of iminium salts by ultraviolet spectroscopy, but these are not definitive as yet (14,25). 

It should be noted that when a BOC-protected amide is subjected to nucleophilic reagents such as MeONa, hydrazine, and LiOH, the amide bond is cleaved in preference to the BOC group (85-96% yield) because of the difference in steric factors. The BOC group can be removed by the methods used to remove it from simple amines. 

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

A large number of nucleophilic substitution reactions involving interconversions of pyridopyrimidines have been reported, the majority of which involve substituents in the pyrimidine ring. This subject has been reviewed previously in an earlier volume in this series which dealt with the theoretical aspects of nucleophilic re-activiti in azines, and so only a summary of the nucelophilic displacements of the substituent groups will be given here. In general, nucleophilic substitutions occur most readily at the 4-position of pyrido-... 

The least squares value for the p constant obtained by this procedure is +6.2 it wiU be obviously subject to change as more meta and epi substituents become available. Only the cata-NO group was excluded from the above plot because it causes a strongly enhanced resonance effect in nucleophilic substitution (Section IV,C, l,a) and an anomalous effect of uncertain origin in the dissociation of carboxylic acids. It can be assumed that the reaction constant for 4-chloro-... 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

Comprehensive work in this field has been done by Slovak authors (98MI1, 95M1359, 96CCC269, 96CCC371, 97CCC99). They prepared 2-substituted (H, Me, Ph) 4-, 5-, 6-, and 7-nitrobenzoxazoles, which were then reduced to amines (not isolated) and subjected to subsequent nucleophilic substitution with activated enol ethers such as alkoxymethylene derivatives of malonic acid esters and nitrile, 3-oxobutanoic acid esters, pentanedione, or cyanoacetic acid esters to yield aminoethylenes 8. 

Dimerization is markedly subject to steric hindrance, thus, whereas 3-n-propylindole dimerizes readily, neither 3-isopropyl- nor Z-tert-butyl-indole dimerizes. This failure is most probably the result of steric hindrance of approach of the electrophilic reagent to position 2 by the bulky 3-substituent in the unprotonated molecule. On the other hand, models show that approach of a nucleophilic reagent to position 2 of a 3-protonated molecule is quite open, it should, there-... 

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