Carbon nucleophiles alkyl halides

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. 

Incidentally, I should say that the thermodynamic data on cobalt(III) indicates that it is a hard acid, but just barely so, and one might say borderline. It is a little harder than tetrahedral carbon and alkyl halides. So hydroxide ion in that sense would be expected perhaps to be a good nucleophilic reagent, as hard acids would like hydroxide ion. 

Due to the presence of a strongly electrophilic carbon centre alkyl halides are susceptible to nucleophilic attack, a nucleophile displaces the halogen as a nucleophilic halide ion (Following fig.). The reaction is called nucleophilic substitution and there are two types of mechanism, i.e. the S I and SN2 mechanisms. Carboxylic acids and carboxylic acid derivatives also undergo nucleophilic substitutions, but the mechanisms are totally different. 

We should compare the S reaction at silicon with the S 2 reaction at carbon. There are some iportant differences. Alkyl halides are soft electrophiles but silyl halides are hard electrophiles. Alkyl halides react only very slowly with fluoride ion but silyl halides react more rapidly with fluoride [than with any other nucleophile. The best nucleophiles for saturated carbon are neutral and/or based on elements down the periodic table (S, Se, I). The best nucleophiles for silicon are charged and based on highly electronegative atoms (chiefly F, Cl, and O). A familiar example is the reaction of enolates at carbon with alkyl halides but at oxygen with silyl chlorides (Chapter 21). 

The polar C—X bond containing an electrophilic carbon makes alkyl halides reactive towards nucleophiles and bases (7.5). 

Figure 5.6 Polarization of 7t C=0 (a) and a C-F (b) orbitals illustrates orbital contributions to the common regiochemistry of nucleophilic reactions at carbon in alkyl halides and carbonyls. Bonds to larger elements do not reflect polarization in the same way (i.e. the C-CI bond in example c) and X-philic attacks become possible. Note that the common ChemDraw representations cannot always accurately describe the shape of antibonding...

TMSLi adds to cyclohexenone in THF-HMPA to give exclusively the 1,4-addition product (eq 3). The intermediate enolate may be stereoselectively alkylated at carbon with alkyl halides, or 0-silylated with chlorotrimethylsilane to provide the enol ether. Nucleophilic 1,4-addition to cyclohexenones is quite stereoselective. Reaction of 5-methylcyclohex-2-enone with TMSLi occurs predominantly by axial attack, resulting in a 92 8 ratio of axial to equatorial products. TMSLi also undergoes diastereoselec-tive nucleophilic addition to 1-naphthyloxazolines (eq 4) however, the addition of the silyl nucleophile is not as selective as the... 

The polymerization of cyclic carbonate with alkyl halide proceeds according to pathway 1 (Scheme 30) and owing to the higher nucleophilicity of the halide anion, the covalent macrohalide is more favored than the trioalkxycarbenium ion. However, when a solvent of higher polarity is used as the reaction medium, partial decarboxylation takes place due to... 

Amines are powerful nucleophiles which react under neutral or slightly basic conditions with several electron-accepting carbon reagents. The reaction of alkyl halides with amines is useful for the preparation of tertiary amines or quaternary ammonium salts. The conversion of primary amines into secondary amines is usually not feasible since the secondary amine tends towards further alkylation. 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

When we discussed elimination reactions in Chapter 5 we learned that a Lewis base can react with an alkyl halide to form an alkene In the present chapter you will find that the same kinds of reactants can also undergo a different reaction one m which the Lewis base acts as a nucleophile to substitute for the halo gen substituent on carbon... 

Nucleophilic substitution reactions of alkyl halides are related to elimination reactions m that the halogen acts as a leaving group on carbon and is lost as an anion The... 

The order of alkyl halide reactivity in nucleophilic substitutions is the same as their order m eliminations Iodine has the weakest bond to carbon and iodide is the best leaving group Alkyl iodides are several times more reactive than alkyl bromides and from 50 to 100 times more reactive than alkyl chlorides Fluorine has the strongest bond to car bon and fluonde is the poorest leaving group Alkyl fluorides are rarely used as sub states m nucleophilic substitution because they are several thousand times less reactive than alkyl chlorides... 

Although this mechanistic picture developed from experiments involving optically active alkyl halides chemists speak even of methyl halides as undergoing nucleophilic substitution with inversion By this they mean that tetrahedral inversion of the bonds to carbon occurs as the reactant proceeds to the product... 

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... 

An advantage that sulfonate esters have over alkyl halides is that their prepara tion from alcohols does not involve any of the bonds to carbon The alcohol oxygen becomes the oxygen that connects the alkyl group to the sulfonyl group Thus the configuration of a sulfonate ester is exactly the same as that of the alcohol from which It was prepared If we wish to study the stereochemistry of nucleophilic substitution m an optically active substrate for example we know that a tosylate ester will have the same configuration and the same optical purity as the alcohol from which it was prepared... 

Anions of acetylene and terminal alkynes are nucleophilic and react with methyl and primary alkyl halides to form carbon-carbon bonds by nucleophilic substitution Some useful applications of this reaction will be discussed m the following section... 

Next an alkyl halide (the alkylating agent) is added to the solution of sodium acetylide Acetylide ion acts as a nucleophile displacing halide from carbon and forming a new carbon-carbon bond Substitution occurs by an 8 2 mechanism... 

The properties of organometallic compounds are much different from those of the other classes we have studied to this point Most important many organometallic com pounds are powerful sources of nucleophilic carbon something that makes them espe cially valuable to the synthetic organic chemist For example the preparation of alkynes by the reaction of sodium acetylide with alkyl halides (Section 9 6) depends on the presence of a negatively charged nucleophilic carbon m acetylide ion... 

Unlike elimination and nucleophilic substitution reactions foimation of oigano lithium compounds does not require that the halogen be bonded to sp hybndized carbon Compounds such as vinyl halides and aiyl halides m which the halogen is bonded to sp hybndized carbon react m the same way as alkyl halides but at somewhat slowei rates... 

A long standing method for the preparation of ethers is the Williamson ether synthesis Nucleophilic substitution of an alkyl halide by an alkoxide gives the carbon-oxygen bond of an ether... 

Step 2 Nucleophilic attack of the halide anion on carbon of the dialkyloxonmm ion This step gives one molecule of an alkyl halide and one molecule of an alcohol... 

Because etiolate anions are sources of nucleophilic carbon one potential use m organic syn thesis IS their reaction with alkyl halides to give a alkyl denvahves of aldehydes and ketones... 

The anion produced by prolon abslraclion from efhyl acefoacefafe is nucleophilic Adding an alkyl halide lo a solulion of fhe sodium sail of efhyl acefoacefafe leads lo alkylalion of fhe a carbon... 

The critical carbon-carbon bond forming step requires nucleophilic substitution on an alkyl halide by an ester enolate Methyl halides are more reactive than... 

Because nitriles can be prepared from alkyl halides by nucleophilic substitution with cyanide ion the overall process RX RC=N RCH2NH2 leads to primary amines that have one more carbon atom than the starting alkyl halide... 

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