Nucleophilic substitution reactions groups

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... 

Representative Functional Group Transformations by Nucleophilic Substitution Reactions of Alkyl Halides... 

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... 

Polymerization via Nucleophilic Substitution Reaction. Halo- and nitro- groups attached to phthahmide groups are strongly activated toward nucleophilic substitution reactions. Thus polyetherimides ate synthesized by the nucleophilic substitution reaction of bishaloimides (59,60) and bisnitroimides (61,62) with anhydrous bisphenol salts in dipolar aptotic solvents. 

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. 

Carbonates undergo nucleophilic substitution reactions analogous to chloroformates except in this case, an OR group (rather than chloride) is replaced by a more basic group. Normally these reactions are cataly2ed by bases. Carbonates are sometimes preferred over chloroformates because formation of hydrogen chloride as a by-product is avoided, which simplifies handling. However, the reactivity of carbonates toward nucleophiles is considerably less than chloroformates. 

In those reactions where the fV-oxide group assists electrophilic or nucleophilic substitution reactions, and is not lost during the reaction, it is readily removed by a variety of reductive procedures and thus facilitates the synthesis of substituted derivatives of pyrazine, quinoxaline and phenazine. 

The nucleophilic substitution reactions in pyrido-[2,3-f>]- and -[3,4-f ]-pyridazines in general follow the usual pattern of polyaza heterocycles. Oxo groups in the 2-, 3- and 6-positions of [2,3-f ]-ones, and in the 2- and 3-positions of [3,4-f ]-ones have been... 

Halogen atoms in the 2-position of imidazoles, thiazoles and oxazoles (542) undergo nucleophilic substitution reactions. The conditions required are more vigorous than those used, for example, for a- and y-halogenopyridines, but much less severe than those required for chlorobenzene. Thus in compounds of type (542 X = Cl, Br) the halogen atom can be replaced by the groups NHR, OR, SH and OH (in the last two instances, the products tautomerize see Sections 4.02.3.7 and 4.02.3.8.1). 

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... 

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-... 

Arynes are intermediates in certain reactions of aromatic compounds, especially in some nucleophilic substitution reactions. They are generated by abstraction of atoms or atomic groups from adjacent positions in the nucleus and react as strong electrophiles and as dienophiles in fast addition reactions. An example of a reaction occurring via an aryne is the amination of o-chlorotoluene (1) with potassium amide in liquid ammonia. According to the mechanism given, the intermediate 3-methylbenzyne (2) is first formed and subsequent addition of ammonia to the triple bond yields o-amino-toluene (3) and m-aminotoluene (4). It was found that partial rearrangement of the ortho to the meta isomer actually occurs. 

The effect of a nitro group at the 6 position on the nucleophilic substitution reaction has been examined using l-methoxy-6-nitroindole (82) as a substrate (2001H1151). The reaction with NaOMe in refluxing DMF generates 6-nitroin-dole (83, 57%), 2-methoxy- (199, 22%), and 3-methoxy-6-nitroindoles (84, 6%) (Scheme 29). The formation of 199 and 84 can be explained by the SN2 -type nucleophilic substitution reaction at the 2 and 3 positions, respectively, with the... 

The nucleophilic substitution reactions are still more limited in scope owing to the instability of the isoxazole ring toward nucleophilic reagents. Homolytic reactions appear to be unknown though some of the reactions being studied are possibly of this type. Besides those reactions which are characteristic of the reactivity of the isoxazole nucleus itself, we shall consider in this section some substitution reactions in the side chain organomagnesium synthesis in the isoxazole series, condensation reactions of the methyl groups of methyl-isoxazoles, and finally some miscellaneous reactions. 

The substitution of fairly labile nucleophilic groups (halogen, methoxy group) in the 3- and 5-positions, and the noncatalytic substitution of the diazonium group at C-4, are to be considered as nucleophilic substitution reactions. As in the benzenoid series, these reactions are believed to proceed in the former case by the Sx2 mechanism and in the latter by the SnI mechanism. 

The nucleophilic substitution of a halogen atom at C-5 in the isoxazole nucleus without further functional substituents is so far unknown, but recently reports appeared on the nucleophilic substitution reactions at C-5 in isoxazole derivatives with benzoyl (78 79), ester, and cyano groups (81—>80, 82) in the 4-position. ... 

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 ... 

Acidic ether cleavages are typical nucleophilic substitution reactions, either SN1 or Sn2 depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an S 2 mechanism, in which or Br attacks the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide. For example, ethyl isopropyl ether yields exclusively isopropyl alcohol and iodoethane on cleavage by HI because nucleophilic attack by iodide ion occurs at the less hindered primary site rather than at the more hindered secondary site. 

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