Nucleophilic substitution examples

Several investigations have demonstrated the possibility or probability of the existence of persistent five- or six-co-ordinate intermediates in the associative pathway for nucleophilic substitution. Examples include the reactions of [AuClJ with thiocyanate and with A-cyclohexylthiobenzamide and of cw-[Pt(N02)2-(NHs)2] with hydrogen bromide. The behaviour of stable five-co-ordinate compounds has been examined with a view to treating them as models for such transient intermediates in associative substitution at four-co-ordinate complexes (see Section 3). A thorough and unusually extensively referenced molecular orbital treatment of... 

A classical reaction leading to 1,4-difunctional compounds is the nucleophilic substitution of the bromine of cf-bromo carbonyl compounds (a -synthons) with enolate type anions (d -synthons). Regio- and stereoselectivities, which can be achieved by an appropiate choice of the enol component, are similar to those described in the previous section. Just one example of a highly functionalized product (W.L. Meyer, 1963) is given. 

Many saturated nitrogen heterocycles are commercially available from industrial processes, which involve, for example, nucleophilic substitution of hydroxyl groum by amino groups under conditions far from laboratory use, e.g. 

In stereoselective antitheses of chiral open-chain molecules transformations into cyclic precursors should be tried. The erythro-configurated acetylenic alcohol given below, for example, is disconnected into an acetylene monoanion and a symmetrical oxirane (M. A. Adams, 1979). Since nucleophilic substitution occurs with inversion of configuration this oxirane must be trens-conilgurated its precursor is commercially available trans-2-butene. 

The Pd—C cr-bond can be prepared from simple, unoxidized alkenes and aromatic compounds by the reaction of Pd(II) compounds. The following are typical examples. The first step of the reaction of a simple alkene with Pd(ll) and a nucleophile X or Y to form 19 is called palladation. Depending on the nucleophile, it is called oxypalladation, aminopalladation, carbopalladation, etc. The subsequent elimination of b-hydrogen produces the nucleophilic substitution product 20. The displacement of Pd with another nucleophile (X) affords the nucleophilic addition product 21 (see Chapter 3, Section 2). As an example, the oxypalladation of 4-pentenol with PdXi to afford furan 22 or 23 is shown. 

The Lewis base that acts as the nucleophile often is but need not always be an anion Neutral Lewis bases can also serve as nucleophiles Common examples of substitutions involving neutral nucleophiles include solvolysis reactions Solvolysis reactions are substitutions m which the nucleophile is the solvent m which the reaction is carried out 8olvolysis m water (hydrolysis) converts an alkyl halide to an alcohol... 

Nucleophilic substitution is one of a variety of mechanisms by which living systems detoxify halogenated organic compounds introduced into the environment Enzymes that catalyze these reactions are known as haloalkane dehalogenases The hydrolysis of 1 2 dichloroethane to 2 chloroethanol for example is a biological nude ophilic substitution catalyzed by a dehalogenase... 

Additional evidence for carbocation intermediates in certain nucleophilic substitutions comes from observing rearrangements of the kind normally associated with such species For example hydrolysis of the secondary alkyl bromide 2 bromo 3 methylbutane yields the rearranged tertiary alcohol 2 methyl 2 butanol as the only substitution product... 

The large rate enhancements observed for bimolecular nucleophilic substitutions m polai aprotic solvents are used to advantage m synthetic applications An example can be seen m the preparation of alkyl cyanides (mtiiles) by the reaction of sodium cyanide with alkyl halides... 

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... 

Section 8 1 Nucleophilic substitution is an important reaction type m synthetic organic chemistry because it is one of the mam methods for functional group transformations Examples of synthetically useful nucleophilic sub stitutions were given m Table 8 1 It is a good idea to return to that table and review its entries now that the details of nucleophilic substitution have been covered... 

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... 

Nucleophilic Substitution Route. Commercial synthesis of poly(arylethersulfone)s is accompHshed almost exclusively via the nucleophilic substitution polycondensation route. This synthesis route, discovered at Union Carbide in the early 1960s (3,4), involves reaction of the bisphenol of choice with 4,4 -dichlorodiphenylsulfone in a dipolar aprotic solvent in the presence of an alkaUbase. Examples of dipolar aprotic solvents include A/-methyl-2-pyrrohdinone (NMP), dimethyl acetamide (DMAc), sulfolane, and dimethyl sulfoxide (DMSO). Examples of suitable bases are sodium hydroxide, potassium hydroxide, and potassium carbonate. In the case of polysulfone (PSE) synthesis, the reaction is a two-step process in which the dialkah metal salt of bisphenol A (1) is first formed in situ from bisphenol A [80-05-7] by reaction with the base (eg, two molar equivalents of NaOH),... 

Nucleophilic Substitutions of Benzene Derivatives. Benzene itself does not normally react with nucleophiles such as haUde ions, cyanide, hydroxide, or alkoxides (7). However, aromatic rings containing one or more electron-withdrawing groups, usually halogen, react with nucleophiles to give substitution products. An example of this type of reaction is the industrial conversion of chlorobenzene to phenol with sodium hydroxide at 400°C (8). 

It is possible to introduce sulfonic acid groups by alternative methods, but these ate Htde used in the dyes industry. However, one worth mentioning is sulfitation, because it provides an example of the introduction of a sulfonic acid group by nucleophilic substitution. The process involves treating an active halogen compound with sodium sulfite. This reaction is used in the purification of m-dinitrohen7ene. 

Fiber-Reactive Dyes. These dyes can enter iato chemical reaction with the fiber and form a covalent bond to become an iategral part of the fiber polymer. They therefore have exceptional wetfastness. Thein main use is on ceUulosic fibers where they are appHed neutral and then chemical reaction is initiated by the addition of alkaH. Reaction with the ceUulose can be by either nucleophilic substitution, using, for example, dyes containing activated halogen substituents, or by addition to the double bond in, for example, vinyl sulfone, —S02CH=CH2, groups. 

In some instances a carbon-carbon bond can be formed with C-nucleophiles. For example, 3-carboxamido-6-methylpyridazine is produced from 3-iodo-6-methylpyridazine by treatment with potassium cyanide in aqueous ethanol and l,3-dimethyl-6-oxo-l,6-dihydro-pyridazine-4-carboxylic acid from 4-chloro-l,3-dimethylpyridazin-6-(lH)-one by reaction with a mixture of cuprous chloride and potassium cyanide. Chloro-substituted pyridazines react with Grignard reagents. For example, 3,4,6-trichloropyridazine reacts with f-butyl-magnesium chloride to give 4-t-butyl-3,5,6-trichloro-l,4-dihydropyridazine (120) and 4,5-di-t-butyl-3,6-dichloro-l,4-dihydropyridazine (121) and both are converted into 4-t-butyl-3,6-dichloropyridazine (122 Scheme 38). 

The possibility of activating the indole nucleus to nucleophilic substitution has been realized by formation of chromium tricarbonyl complexes. For example, the complex from TV-methylindole (215) undergoes nucleophilic substitution with 2-lithio-l,3-dithiane to give a product (216) which can be transformed into l-methylindole-7-carbaldehyde (217) (78CC1076). 

Alkylthio groups are replaced in nucleophilic substitutions. Such reactions are easy in cationic derivatives for example, in the 1,2-dithiolylium series (539), substituted cydopen-tadienyl ion gives fulvene derivatives (540) (66AHC(7)39). 2-Methylthio groups in... 

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). 

The classification can be illustrated with a few examples. All of the nucleophilic substitutions shown in Scheme 3.4 are of the exo-tet classification. The reacting atom is of sp hybridization (tetrahedral = tet), and the reacting bond, that is, the bond to the leaving grov, is exocyclic to the forming ring ... 

The points that we have emphasized in this brief overview of the S l and 8 2 mechanisms are kinetics and stereochemistry. These features of a reaction provide important evidence for ascertaining whether a particular nucleophilic substitution follows an ionization or a direct displacement pathway. There are limitations to the generalization that reactions exhibiting first-order kinetics react by the Sj l mechanism and those exhibiting second-order kinetics react by the 8 2 mechanism. Many nucleophilic substitutions are carried out under conditions in which the nucleophile is present in large excess. When this is the case, the concentration of the nucleophile is essentially constant during die reaction and the observed kinetics become pseudo-first-order. This is true, for example, when the solvent is the nucleophile (solvolysis). In this case, the kinetics of the reaction provide no evidence as to whether the 8 1 or 8 2 mechanism operates. 

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. 

Examples of effects of reactant stmcture on the rate of nucleophilic substitution reactions have appeared in the preceding sections of this chapter. The general trends of reactivity of primaiy, secondary, and tertiaiy systems and the special reactivity of allylic and benzylic systems have been discussed in other contexts. This section will emphasize the role that steric effects can pl in nucleophilic substitution reactions. 

Nucleophilic substitution in cyclohexyl systems is quite slow and is often accompanied by extensive elimination. The stereochemistry of substitution has been determined with the use of a deuterium-labeled substrate (entry 6). In the example shown, the substitution process occurs with complete inversion of configuration. By NMR amdysis, it can be determined that there is about 15% of rearrangement by hydride shift accon any-ing solvolysis in acetic acid. This increases to 35% in formic acid and 75% in trifiuoroacetic acid. The extent of rearrangement increases with decreasing solvent... 

A classic example of neighboring-group participation involves the solvolysis of compounds in which an acetoxy substituent is present next to a carbon that is undergoing nucleophilic substitution. For example, the rates of solvolysis of the cis and trans isomers of 2-acetoxycyclohexyl p-toluenesulfonate differ by a factor of about 670, the trans compound being the more reactive one ... 

There are several reaction sequences which involve such intramolecular hydrogen abstraction steps. One example is the photolytically intitiated decomposition of N-haloamines in acidic solution, which is known as the Hofinann-Loffier reactionThe reaction leads initially to y-haloamines, but these are usually converted to pyrrolidines by intramolecular nucleophilic substitution ... 

Benzylic carbon-hydrogen bonds in compounds such as methylpentafluoro-benzene, fluoromethylpentafluorobenzene, and difluoromethylpentafluoroben-zene are not capable of metalation by butyllithium Instead nucleophilic substitution of the para fluorines occurs m each example [55] (equation 13)... 

The strength of their- car bon-halogen bonds causes aryl halides to react very slowly in reactions in which carbon-halogen bond cleavage is rate-detenrrining, as in nucleophilic substitution, for example. Later in this chapter we will see exanples of such reactions that do take place at reasonable rates but proceed by mechanisms distinctly different from the classical SnI and Sn2 pathways. 

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