Nucleophilic substitution reactions leaving groups

Among the reactive groups in wool the most important are amino, imino, and hydroxyl groups. Reactions occur in a weakly acidic medium (pH 3-5) and include nucleophilic substitution of leaving groups (usually Cl, F, and, rarely, sulfonate or ammonium groups) or addition reactions to polar aliphatic double bonds. 

The formation of halides by the nucleophilic substitution of leaving groups is commonly used in the synthesis of more elaborate structures. The synthesis of inexpensive bulk chemicals like solvents, however, is mostly done by oxidation or addition reactions. Halides are either used as intermediates or are valuable end products. Authors of publications, especially patent literature, often claim one reaction for three or even four halogens. In practice, this rarely holds true and each of the halogens quite often requires different conditions. The usual order of halide nucleophilicity is I" > Br > Cl > F". In dimethyl-formamide the reverse order Cl > Br > I is observed. This order goes along with the order of the basic... 

Leaving group The group of atoms (coded green in this text) displaced in a substitution reaction. Leaving-group ability The ease with which a group can be displaced in a nucleophilic substitution,... 

Nomenclature Physical properties Interesting alkyl halides The polar carbon-halogen bond General features of nucleophilic substitution The leaving group The nucleophile Possible mechanisms for nucleophilic substitution Two mechanisms for nucleophilic substitution The S 2 mechanism Application Useful Snj2 reactions... 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

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 reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

Overall the stereospecificity of this method is the same as that observed m per oxy acid oxidation of alkenes Substituents that are cis to each other m the alkene remain CIS m the epoxide This is because formation of the bromohydrm involves anti addition and the ensuing intramolecular nucleophilic substitution reaction takes place with mver Sion of configuration at the carbon that bears the halide leaving group... 

Isopentenyl pyrophosphate and dimethylallyl pyrophosphate are structurally sim liar—both contain a double bond and a pyrophosphate ester unit—but the chemical reactivity expressed by each is different The principal site of reaction m dimethylallyl pyrophosphate is the carbon that bears the pyrophosphate group Pyrophosphate is a reasonably good leaving group m nucleophilic substitution reactions especially when as in dimethylallyl pyrophosphate it is located at an allylic carbon Isopentenyl pyrophosphate on the other hand does not have its leaving group attached to an allylic carbon and is far less reactive than dimethylallyl pyrophosphate toward nucleophilic reagents The principal site of reaction m isopentenyl pyrophosphate is the carbon-carbon double bond which like the double bonds of simple alkenes is reactive toward electrophiles... 

Nucleophilic aliphatic substitution (Chapter 8) Reaction m which a nucleophile replaces a leaving group usually a halide ion from sp hybridized carbon Nucleophilic aliphatic substitution may proceed by either an S l or an Sfj2 mechanism... 

Nucleophilic aromatic substitution (Chapter 23) A reaction m which a nucleophile replaces a leaving group as a sub stituent on an aromatic nng Substitution may proceed by an addition-elimination mechanism or an elimination-addition mechanism... 

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. 

If the fV-aryl group is strongly activated, then it can be removed in nucleophilic substitution reactions in which the azole anion acts as leaving group. Thus l-t2,4-dinitrophenyl)pyrazole reacts with N2H4 or NaOMe. 

Trifluoromethanesulfonate (triflate) ion is an exceptionally good leaving grov. It can be used for nucleophilic substitution reactions on unreactive substrates. Acetolysis of cyclopropyl triflate, for example, occurs 10 times faster than acetolysis of cyclopropyl tosylate. Table 5.11 gives a conqiarison of the triftate group with some other common leaving groups. 

Fluonde Ion as Nucleophile and a Leaving Group in Aromatic Nucleophilic Substitution Reactions Vlasov V M J Fluorine Chem 6i. 193-216 77... 

An a-halosulfone 1 reacts with a base by deprotonation at the a -position to give a carbanionic species 3. An intramolecular nucleophilic substitution reaction, with the halogen substituent taking the part of the leaving group, then leads to formation of an intermediate episulfone 4 and the halide anion. This mechanism is supported by the fact that the episulfone 4 could be isolated. Subsequent extrusion of sulfur dioxide from 4 yields the alkene 2 ... 

The -R and -H in these compounds can Tact as leaving groups in nucleophilic substitution reactions. 

The -OH, -X, -OR, -SR, -NH2, -0C0R, and -0P032- in these compounds can act as leaving groups in nucleophilic substitution reactions. 

A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl- in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate. 

Tosylate (Section 11.1) A p-toluenesulfonate ester useful as a leaving group in nucleophilic substitution reactions. 

Several distinct mechanisms are possible for aliphatic nucleophilic substitution reactions, depending on the substrate, nucleophile, leaving group, and reaction conditions. In all of them, however, the attacking reagent carries the electron pair with it, so that the similarities are greater than the differences. Mechanisms that occur at a saturated carbon atom are considered first. By far the most common are the SnI and Sn2 mechanisms. 

Certain nucleophilic substitution reactions that normally involve carbocations can take place at norbomyl bridgeheads (though it is not certain that carbocations are actually involved in all cases) if the leaving group used is of the type that cannot function as a nucleophile (and thus come back) once it has gone, for example. 

So far, we have explored the substrate, the nucleophile, and the leaving group. This takes care of all of the parts of the compounds that are reacting with each other. Let s summarize substitution reactions in a way that allows us to see this ... 

---