Nucleophilic substitution reactions Nucleophilicity

Know the meaning of nucleophilic substitution reaction, nucleophile, substrate, leaving group. 

Nucleophilic substitution reactions. Nucleophilic displacement of a halogen In compounds such as 2-acetamldo-4-chloromethylthlazole under reflux of an alkaline ethanol solution Is a straight foreward reaction (219). Nucleophilic aromatic substitution reactions are more complex but under certain conditions they can be used for single step synthesis of aryl methyl sulfides. A number of 4-methylthlo-polychlorobiphenyls were synthesized from... 

Other Nucleophilic Substitution Reactions. Nucleophilic substitution of a variety of substituted aminoiminomethanesulfonic acids with cyanide leads to the corresponding aminoimi-noethanenltrlles in 30-87% yield. A number of substituted aminoiminomethanesulfonic acids react with sodium azide in acetic acid to give the corresponding 5-aminotetrazole. This reaction Is subject to pronounced steric hindrance. Hydroxyl-amine and cyanamlde also give nucleophilic substitution of the sulfonic acid group. ... 

Aryl halides are less reactive than alkyl halides in nucleophilic substitution reactions. Nucleophilic substitution in aryl halides is facilitated by the presence of a strong electron-withdrawing group, such as NOj, ortho or para to the halogen. 

As the reaction shown in the scheme above is a nucleophilic substitution reaction, nucleophilicity of oxygen atoms in monomers and polymer units is an important factor governing the competition between chain propagation and chain transfer to polymer. 

The attack by a reagent of a molecule might be hampered by the presence of other atoms near the reaction site. The larger these atoms and the more are there, the higher is the geometric restriction, the steric hindrance, on reactivity. Figure 3-6e illustrates this for the attack of a nucleophile on the substrate in a nucleophilic aliphatic substitution reaction. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

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. 

The nucleophilic reactivity of 2-halogenothiazoles is strongly affected by the substituent effect, depending on the kind of substitution reaction. Positions 4 and 5 can be considered as meta and para , respectively, with regard to carbon 2 and to groups linked to it consequently, it is possible to correlate the reactivity data with Hammett s relationships. 

TABLE v-3. p VALUES FOR SOME SUBSTITUTION REACTIONS OF 2-HALOGENO-X-THIAZOLES WITH SUBSTirUTED NUCLEOPHILES... 

Many 2-substituted 5-nitrothiazoles are prepared (by nucleophilic substitution reactions on 2-halogeno-5-nitrothiazoles) for use as biocides or for their biological activity (31, 91-95). 

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... 

Primary carbocations are so high m energy that their intermediacy m nucleophilic substitution reactions is unlikely When ethyl bromide undergoes hydrolysis m aqueous formic acid substitution probably takes place by an 8 2 like process m which water is the nucleophile... 

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... 

Each of the following nucleophilic substitution reactions has been reported in the chemical literature Many of them involve reactants that are somewhat more complex than those we have dealt with to this point Nevertheless you should be able to predict the product by analogy to what you know about nucleophilic substitution in simple systems... 

Alkynes of the type RC CH may be prepared by nucleophilic substitution reactions in which one of the starting matenals is sodium acetyhde (Na" C=CH)... 

As m other nucleophilic substitution reactions alkyl p toluenesulfonates may be used m place of alkyl halides... 

If the Lewis base ( Y ) had acted as a nucleophile and bonded to carbon the prod uct would have been a nonaromatic cyclohexadiene derivative Addition and substitution products arise by alternative reaction paths of a cyclohexadienyl cation Substitution occurs preferentially because there is a substantial driving force favoring rearomatization Figure 12 1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution For electrophilic aromatic substitution reactions to... 

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... 

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... 

This reaction is of synthetic value in that a halo acids are reactive sub strates m nucleophilic substitution reactions... 

The reaction of ammonia and amines with esters follows the same general mech anistic course as other nucleophilic acyl substitution reactions (Figure 20 6) A tetrahe dral intermediate is formed m the first stage of the process and dissociates m the second stage... 

Amides are the least reactive caiboxyhc acid deiivative and the only nucleophilic acyl substitution reaction they undeigo is hydrolysis Amides are fanly stable m water but the amide bond is cleaved on heating m the presence of strong acids 01 bases Nomi nally this cleavage produces an amine and a caiboxyhc acid... 

Alkylamines are in principle capable of being prepared by nucleophilic substitution reactions of aUtyl halides with ammonia... 

Noticeably absent from Table 23 3 are nucleophilic substitutions We have so far seen no nucleophilic substitution reactions of aryl halides m this text Chlorobenzene for example is essentially inert to aqueous sodium hydroxide at room temperature Reac tion temperatures over 300°C are required for nucleophilic substitution to proceed at a reasonable rate... 

A nitro group behaves the same way m both reactions it attracts electrons Reaction is retarded when electrons flow from the aromatic ring to the attacking species (electrophilic aromatic substitution) Reaction is facilitated when electrons flow from the attacking species to the aromatic ring (nucleophilic aromatic substitution) By being aware of the connection between reactivity and substituent effects you will sharpen your appreciation of how chemical reactions occur... 

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... 

Nucleophilicity (Section 8 7) A measure of the reactivity of a Lewis base in a nucleophilic substitution reaction... 

Substitution Reactions on Side Chains. Because the benzyl carbon is the most reactive site on the propanoid side chain, many substitution reactions occur at this position. Typically, substitution reactions occur by attack of a nucleophilic reagent on a benzyl carbon present in the form of a carbonium ion or a methine group in a quinonemethide stmeture. In a reversal of the ether cleavage reactions described, benzyl alcohols and ethers may be transformed to alkyl or aryl ethers by acid-catalyzed etherifications or transetherifications with alcohol or phenol. The conversion of a benzyl alcohol or ether to a sulfonic acid group is among the most important side chain modification reactions because it is essential to the solubilization of lignin in the sulfite pulping process (17). 

Substitution reactions on dialkyl peroxides without concurrent peroxide cleavage have been reported, eg, the nitration of dicumyl peroxide (44), and the chlorination of di-/ fZ-butyl peroxide (77). Bromination by nucleophilic displacement on a-chloro- or a-hydroxyalkyl peroxides with hydrogen bromide produces a-bromoalkyl peroxides (78). 

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. 

Substitution Reactions. Aromatic heterocycHc A/-oxides undergo both electrophilic and nucleophilic substitution because the dipolar N-oxide group is both an electron donor and an electron acceptor, giving rise to the resonance stmctures ... 

Reactions. In general, isoquiaoline undergoes electrophilic substitution reactions at the 5-position and nucleophilic reactions at the 1-position. Nitration with mixed acids produces a 9 1 mixture of 5-nitroisoquiaoline [607-32-9] and 8-nitroisoquinoline [7473-12-3]. The ratio changes slightiy with temperature (143,144). Sulfonation of isoquiaoline gives a mixture with 5-isoquiaolinesulfonic acid [27655-40-9] as the principal product. 

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