Nucleophiles and elimination

There are other instances, however, where unusually large extents of elimination are encountered which cannot be explained in this way. An example is provided by a study of the nucleophilic and elimination reactions of the dipentamethyl benzhydryl cation 69.247 Comparisons of pA"R values (from extrapolations based on the HR acidity function) with those of the unmethylated and partially methylated benzhydryl cations shown below, indicate that methylation cumulatively stabilizes the cation relative to the alcohol (possibly in part because the latter is destabilized by steric congestion). 

The overall result of addition of a nucleophile and elimination of a leaving group is substitution of the nucleophile for the leaving group. Recall from Chapter 20 that nucleophilic substitution occurs with carbanions (R ) and hydride (H ) as nucleophiles. A variety of oxygen and nitrogen nucleophiles also participate in this reaction. 

A carbocationic intermediate is formed in both the SnI and the El mechanisms. After the carbocation is formed, addition of a nucleophile leads to an overall substitution reaction, whereas fragmentation leads to an overall elimination reaction, so there is a competition between the two modes of reaction. It is possible to predict whether substitution or elimination dominates, just as it is possible to predict whether Sn2 or E2 will predominate under basic conditions. Predicting which pathway dominates is easier under acidic conditions, though. Addition is favored in hydroxylic (i.e., nucleophilic) solvents (RCO2H, ROH, II2O) and when the nucleophile is contained in the same molecule, whereas fragmentation is favored in aprotic solvents. In other words, substitution occurs when the carbocation intermediate can be rapidly intercepted by a nucleophile, and elimination occurs when it cannot. 

There are three important reactions of carbocations rearrangements, addition of a nucleophile, and elimination, usually of a proton. Since rearrangements involve conversion of one carbocation into another, these reactions will need to be completed to give an uncharged product by addition of a nucleophile or by elimination. 

Chemical agents enhance and inhibit chemical carcinogenesis by a variety of mechamisms (Table I). These Include modification of carcinogen availability, bioactivation, reactive interactions, depletion of cytoprotective cellular nucleophiles, and elimination processes. 

It is apparent from section 2.5 that many factors influence the course of nucleophilic reactions, including the nature of the nucleophile, its strength, the solvent, the substrate and the nature of the leaving group. When substitution (sec. 2.7.A,B) and elimination (sec. 2.9.A,B) are discussed, it will be noted that they are sometimes competitive when using nucleophiles that are also bases, such as hydroxide. The same factors mentioned above influence the extent of this competition. If the functional groups in a molecule were such that substitution and elimination were competitive processes, then a mixture of products could result. It would be very useful to have a list of parameters for such situations that allow one to make predictions. This section will focus on several factors that influence both nucleophilic and elimination reactions. Analysis of these factors lead to key assumptions and predictions of the major product in many cases. 

As expected, N-, 0-, S- and C-nucleophiles attack the ring C-atoms of pyridine. Addition of the nucleophile and elimination of a pyridine substituent as leaving group occur in a two-step process, i.e. in an S Ar reaction with regeneration of the heterarene system. S Ar reactions in pyridine occur preferably in the 2- and 4-positions and less readily in the 3-position, as indicated by studies of relative reactivity of halopyridines (e.g. chloropyridine + NaOEt in EtOH at 20°C relative reaction rates 2-Cl 0.2, 4-C1=1,3-C1 10-5). 

Mixed anhydrides can be formed by reaction of the acid chloride of one carboxylic acid with a different carboxylic acid in the presence of a base the mechanism involves the addition of the carboxylate nucleophile and elimination of the chloride leaving group from the resulting CTI. 

Answer The sterically hindered r r -butoxide ion is a poorer nucleophile, and elimination is favored by default. 

N,N,N, N -tetramethyl-l,8,-naph-thalenediamiDe M.P. 51 C. A remarkably strong mono-acidic base (pKg 12-3) which is almost completely non-nucleophilic and valuable for promoting organic elimination reactions (e.g. of alkyl halides to alkenes) without substitution. 

Two efficient syntheses of strained cyclophanes indicate the synthetic potential of allyl or benzyl sulfide intermediates, in which the combined nucleophilicity and redox activity of the sulfur atom can be used. The dibenzylic sulfides from xylylene dihalides and -dithiols can be methylated with dimethoxycarbenium tetrafiuoroborate (H. Meerwein, 1960 R.F. Borch, 1968, 1969 from trimethyl orthoformate and BFj, 3 4). The sulfonium salts are deprotonated and rearrange to methyl sulfides (Stevens rearrangement). Repeated methylation and Hofmann elimination yields double bonds (R.H. Mitchell, 1974). 

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

Among several propargylic derivatives, the propargylic carbonates 3 were found to be the most reactive and they have been used most extensively because of their high reactivity[2,2a]. The allenylpalladium methoxide 4, formed as an intermediate in catalytic reactions of the methyl propargylic carbonate 3, undergoes two types of transformations. One is substitution of cr-bonded Pd. which proceeds by either insertion or transmetallation. The insertion of an alkene, for example, into the Pd—C cr-bond and elimination of/i-hydrogen affords the allenyl compound 5 (1.2,4-triene). Alkene and CO insertions are typical. The substitution of Pd methoxide with hard carbon nucleophiles or terminal alkynes in the presence of Cul takes place via transmetallation to yield the allenyl compound 6. By these reactions, various allenyl derivatives can be prepared. 

Section 8 13 When nucleophilic substitution is used for synthesis the competition between substitution and elimination must be favorable However the normal reaction of a secondary alkyl halide with a base as strong or stronger than hydroxide is elimination (E2) Substitution by the Sn2 mechanism predominates only when the base is weaker than hydroxide or the alkyl halide is primary Elimination predominates when tertiary alkyl halides react with any anion... 

The acidity of acetylene and terminal alkynes permits them to be converted to their conjugate bases on treatment with sodium amide These anions are good nucleophiles and react with methyl and primary alkyl halides to form carbon-carbon bonds Secondary and tertiary alkyl halides cannot be used because they yield only elimination products under these conditions... 

Primary benzyhc halides are ideal substrates for Sn2 reactions because they are very reactive toward good nucleophiles and cannot undergo competing elimination... 

A number of compounds of the general type H2NZ react with aldehydes and ketones m a manner analogous to that of primary amines The carbonyl group (C=0) IS converted to C=NZ and a molecule of water is formed Table 17 4 presents exam pies of some of these reactions The mechanism by which each proceeds is similar to the nucleophilic addition-elimination mechanism described for the reaction of primary amines with aldehydes and ketones... 

Cycloalkene (Section 5 1) A cyclic hydrocarbon characterized by a double bond between two of the nng carbons Cycloalkyne (Section 9 4) A cyclic hydrocarbon characterized by a tnple bond between two of the nng carbons Cyclohexadienyl anion (Section 23 6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism It is represented by the general structure shown where Y is the nucleophile and X is the leaving group... 

The first three chapters discuss fundamental bonding theory, stereochemistry, and conformation, respectively. Chapter 4 discusses the means of study and description of reaction mechanisms. Chapter 9 focuses on aromaticity and aromatic stabilization and can be used at an earlier stage of a course if an instructor desires to do so. The other chapters discuss specific mechanistic types, including nucleophilic substitution, polar additions and eliminations, carbon acids and enolates, carbonyl chemistry, aromatic substitution, concerted reactions, free-radical reactions, and photochemistry. 

An example of cleavage ol the sulfur-oxygen bond in trifluoromethane-sulfonic ester has been reported Tnfluororaethyl triflate reacts with neutral or anionic nucleophiles with elimination of carbonyl difluoride and formation of trifluoromethanesulfonyl fluoride [57] (equation 32) The mechanism of this reaction involves elimination of fluoride ion, which is a chain carrier in the substitution of fluorine for the trifluoromethoxy group... 

Fluoride ion produced from the nucleophilic addition-elimination reactions of fluoroolefins can cataly7e isomerizations and rearrangements The reaction of per fluoro-3-methyl-l-butene with dimethylamine gives as products 1-/V,/Vdimeth-ylamino-1,1,2,2,4,4,4-heptafluoro-3-trifluoromethylbutane, N,W-dimetliyl-2,2,4,4,4-pentafluoro 3 trifluoromethylbutyramide, and approximately 3% of an unidentified olefin [10] The butylamide results from hydrolysis of the observed tertiary amine, and thus they share a common intermediate, l-Al,A -dimethylamino-l,l 24 44-hexafluoro-3-trifluoromethyl-2-butene, the product from the initial addition-elimination reaction (equation 4) The expected product from simple addition was not found... 

FIGURE 8.11 When a Lewis base reacts with an alkyl halide, either substitution or elimination can occur. Substitution (Sn2) occurs when the Lewis base acts as a nucleophile and attacks carbon to displace bromide. Elimination (E2) occurs when the Lewis base abstracts a proton from the p carbon. The alkyl halide shown is isopropyl bromide, and elimination (E2) predominates over substitution with alkox-ide bases. 

Conversion to p-toluenesulfonate esters (Section 8.14) Alcohols react with p-toluenesulfonyl chloride to give p-toluenesulfonate esters. Sulfonate esters are reactive substrates for nucleophilic substitution and elimination reactions. The p-toluenesulfonate group is often abbreviated —OTs. 

Nucleophilic substitution by cyanide ion (Sections 8.1, 8.13) Cyanide ion is a good nucleophile and reacts with alkyl halides to give nitriles. The reaction is of the S m2 type and is limited to primary and secondary alkyl halides. Tertiary alkyl halides undergo elimination aryl and vinyl halides do not react. 

Cyclohexadienyl anion (Section 23.6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism. It is represented by the general structure shown, where Y is the nucleophile and X is the leaving group. 

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