Carbon nucleophiles, substitution

Imidazole reactivity was fully covered in CHEC-I, and only a brief summary is included here. The neutral molecule is Jt-excessive, being subject to electrophilic attack at N-3, less readily at C-4(5), and seldom at C-2. In benzimidazole electrophiles preferentially attack N-3 and the benzene ring carbons. Nucleophilic substitution reactions usually require some form of electron withdrawal elsewhere in the system, with displacements of groups at C-2 often favored. Imidazolium species are naturally more susceptible to nucleophilic attack, and they only undergo electrophilic substitutions with difficulty (e.g. nitration, sulfonation). The corresponding imidazole anions, when they can form, are highly reactive towards electrophiles. 

Dichlorobenzene)FeCp reacts with diethylmalonate only once due to in situ deprotonation of the product addition of excess MeOH or methylthioglycolate allows disubstitution [66]. (Nitroarene)FeCp complexes have also been used with carbon nucleophiles [87] and again reactivity similar to the chloroarene complexes is observed. Application of carbon nucleophile substitution chemistry for the synthesis of heterocycles such as 36 is described [88]. 

Leaving group effects on the ratio of C- to O-alkylation can be correlated by reference to the hard-soft-acid-base (HSAB) rationale. Of the two nucleophilic sites in an enolate ion, oxygen is harder than carbon. Nucleophilic substitution reactions of the Sn2 type proceed best when the nucleophile and leaving group are either both hard or both soft. Consequently, ethyl iodide, with the very soft leaving... 

Alkenes in (alkene)dicarbonyl(T -cyclopentadienyl)iron(l+) cations react with carbon nucleophiles to form new C —C bonds (M. Rosenblum, 1974 A.J. Pearson, 1987). Tricarbon-yi(ri -cycIohexadienyI)iron(l-h) cations, prepared from the T] -l,3-cyclohexadiene complexes by hydride abstraction with tritylium cations, react similarly to give 5-substituted 1,3-cyclo-hexadienes, and neutral tricarbonyl(n -l,3-cyciohexadiene)iron complexes can be coupled with olefins by hydrogen transfer at > 140°C. These reactions proceed regio- and stereospecifically in the successive cyanide addition and spirocyclization at an optically pure N-allyl-N-phenyl-1,3-cyclohexadiene-l-carboxamide iron complex (A.J. Pearson, 1989). 

Pd(II) compounds coordinate to alkenes to form rr-complexes. Roughly, a decrease in the electron density of alkenes by coordination to electrophilic Pd(II) permits attack by various nucleophiles on the coordinated alkenes. In contrast, electrophilic attack is commonly observed with uncomplexed alkenes. The attack of nucleophiles with concomitant formation of a carbon-palladium r-bond 1 is called the palladation of alkenes. This reaction is similar to the mercuration reaction. However, unlike the mercuration products, which are stable and isolable, the product 1 of the palladation is usually unstable and undergoes rapid decomposition. The palladation reaction is followed by two reactions. The elimination of H—Pd—Cl from 1 to form vinyl compounds 2 is one reaction path, resulting in nucleophilic substitution of the olefinic proton. When the displacement of the Pd in 1 with another nucleophile takes place, the nucleophilic addition of alkenes occurs to give 3. Depending on the reactants and conditions, either nucleophilic substitution of alkenes or nucleophilic addition to alkenes takes place. 

The allyl-substituted cyclopentadiene 122 was prepared by the reaction of cyclopentadiene anion with allylic acetates[83], Allyl chloride reacts with carbon nucleophiles without Pd catalyst, but sometimes Pd catalyst accelerates the reaction of allylic chlorides and gives higher selectivity. As an example, allylation of the anion of 6,6-dimethylfulvene 123 with allyl chloride proceeded regioselectively at the methyl group, yielding 124[84]. The uncatalyzed reaction was not selective. 

When a bidentate phosphine is used as a ligand for the reaction of J-keto esters or /i-diketones, no dimerization takes place. Only a 2-butenyl group is introduced to give 68[49,62], Substituted dienes such as isoprene, 1,3-cyclohexa-diene, and ocimene react with carbon nucleophiles to give a mixture of possible regio- and stereoisomers of 1 1 adducts when dppp is used as a ligand[63,64]. 

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. 

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

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. 

Bromide ion forms a bond to the primary carbon by pushing off a water molecule This step IS bimolecular because it involves both bromide and heptyloxonium ion Step 2 IS slower than the proton transfer m step 1 so it is rate determining Using Ingold s ter mmology we classify nucleophilic substitutions that have a bimolecular rate determining step by the mechanistic symbol Sn2... 

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... 

FIGURE 8 2 Hybrid orbital description of the bonding changes that take place at carbon during nucleophilic substitution by the Sn2 mechanism... 

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... 

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... 

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... 

Next in what amounts to an intramolecular Williamson ether synthesis the alkoxide oxygen attacks the carbon that bears the halide leaving group giving an epoxide As m other nucleophilic substitutions the nucleophile approaches carbon from the side oppo site the bond to the leaving group... 

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... 

A naturally occurring sulfonium salt S adenosylmethionme (SAM) is a key sub stance in certain biological processes It is formed by a nucleophilic substitution m which the sulfur atom of methionine attacks the primary carbon of adenosine triphosphate dis placing the triphosphate leaving group as shown m Figure 16 7... 

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