Nucleophilic 1,3-substitutions

Substitutions of Sn2 type are frequently used for carbon-carbon or carbon-heteroatom bond formation. However, little attention has been devoted to the development of such reactions in water. This is likely due to concerns about competitive hydrolysis of the electrophile in water and SN2-type reactions being slower in aqueous conditions than in aprotic polar solvents due to the higher cost of desolvation of nucleophiles. We shall discuss the ring opening of epoxides and aziridines, palladium-catalyzed allylic substitutions, as well as acylations and sulfonylations of amines and alcohols. 

Nucleophilic substitutions proceeding via Sn2 pathways can be activated by pressure, as has been demonstrated in many examples. In particular, the ring opening of epoxides can be initiated by pressure, and also by Lewis acid catalysis. Consequently, combining these two activation modes might lead to an even more effective way to functionalize epoxides, and indeed, this strategy has been successfully applied. 

Nucleophilic Substitution.—The replacement of halogen in 2-bromo-5-carboxy-4-methylthiazoles (51 R = EtO or PhNH) by a wide variety of nucleophiles (including phenols, thiophenols, dithiocarbamic acids, and sulphinic acids) has provided the appropriate derivatives (52) in high yields, but some anomalies were observed. The products included examples incorporating 1,3,4-thiadiazole or benzothiazole nuclei in the 2-position of 

Nucleophilic replacement of nitro- by fluoro-groups, by the action of potassium fluoride in N-methyl-2-pyrrolidone, provides 2-fluorothiazole, which is difficultly accessible by other means.  

Bimolecular nucleophilic Sj.j2 substitution proceeds with inversion of configuration of an electropositive atom with an attached leaving group. When the leaving group is identical to that of the nucleophile, the absolute configuration of a stereogenic 

Wang polymer-CH2P(C6Hs)3Br lipase (Altus-17) 

Desymmetrization of 1,2-diols is one of the most important methodologies for synthesizing chiral building blocks. Although monoacylation of meso-diols is the straightforward method, monoacylated products might be racemized during 

Most asymmetric reactions catalysed by metal complexes proceed via a multistep mechanism. The stereo-determining step must be carefully identified. Sometimes the (R)- and (S)-enantiomers of a racemic substrate react at almost the same 

The only example of nucleophilic substitution in the pyrrole ring is the treatment of the chloropyrroloquinoline (75) with methyl magnesium iodide or tin and hydrochloric acid (nucleophilic substitution by hydride). However, the structures of these three compounds have never been rigorously proved. 

The two main mechanisms for nucleophilic substitution of alkyl halides are SN1 and SN2. These represent the extreme mechanisms of nucleophilic substitution, and some reactions involve mechanisms which lie somewhere in between the two. 

In both SN1 and SN2 reactions, the mechanisms involve the loss of the halide anion (X-) from RX. The halide anion that is expelled is called the leaving group. 

This is a concerted (one-step) mechanism in which the nucleophile forms a new bond to carbon at the same time as the bond to the halogen atom (X) is broken. The reaction is second order, or bimoiecuiar, as the rate depends on the concentration of both the nucleophile (Nu) and the halogenoalkane (RX). 

The reaction leads to an inversion (or change) of stereochemistry at a chiral centre (i.e. an / -enantiomer will be converted into an 5-enantiomer). This is known as a Walden inversion. 

The charge is spread from the nucleophile (Nu) to the leaving group (X). The carbon atom in the T.S. is partially bonded to both Nu and X 

General base catalysis in simple systems is typically a default mechanism, observed in the absence of strong acid or base, or nucleophilic alternatives. It is a relatively inefficient and often slow process, readily observed only with specially designed or activated substrates. The simplest way of increasing reactivity without using unnatural activated functional groups is to make reactions intramolecular. Systems where the general base catalysis is itself intramolecular are discussed below, in Section 2.3.5 we discuss here systems where the nucleophilic reaction it supports is intramolecular - that is, a cyclization reaction. 

General base catalysis of the Sn2 reaction is not generally observed, for various reasons. Amine nucleophiles do not need it, and hydroxy groups are very weakly nucleophilic towards soft, polarisable centers like sp -carbon. The only well-authenticated example of an intermolecular general base catalyzed nucleophilic displacement at sp -hybridized carbon is the trifluoroethanolysis of the benzylsul- 

For positively charged aromatic systems, a high degree of reactivity toward nucleophiles would be expected at the positions a or y to the positively charged nitrogen atom. Thus, substitution should occur at positions 

The earliest struggles to place the study of organic chemistry into a position where it was possible to predict the outcome of a reaction, by understanding the path between a starting material and product, involved substitution reactions. 

In 1854, a year after his death, the publication of the landmark work of Auguste Laurent, which codified and extended the ideas of Dumas, set firmly in place the concept of the retention of a central, unchanging molecular core and attached replaceable substituents. 

About the same time (1850), Wilhelmy undertook to measure the rate at which acid-converted cane sugar to fruit sugar. This study is arguably the first in which the mathematics for a first-order process (Chapter 4) was deduced. 

Although it appears that the kinetic work of WUhehny was largely ignored, substitution reactions, converting one material into another, continued to 

Hlie chemistry of the conversion of the disaccharide sucrose ([a]o = +66.5) to the monosaccharide fructose ([a]D = -92.4) and an equilibrium mixture of a-D-glucopyranose (a-D-glucose) and its anomer, (i-D-glucopyranose (p-D-glucose) ([ajo = +52.7 for the mixture), the structures of which were unknown at the time, will be discussed in Chapter 11. The positive rotation of the mixture of glucose epimers is less than the high negative rotation of fructose. 

Under appropriate conditions 1,2-unsubstituted 1,2-dihydro- and 2,4-unsubstituted 2,4-dihydropyrazol-3-ones take part in nucleophilic substitutions at N2. In 2,4-dihydropyrazol-3-ones substituted at N1 nucleophilic substitution occurs at C4 as 

Nucleophilic aromatic substitution of activated aryl halides has been reported for both 1,2-dihydro and 2,4-dihydropyrazol-3-ones. With 2-fluorobenzonitrile 544 pyrazol-3-one 543 required heating at 100 °C for 16 h in dimethyl sulfoxide in the 

The reaction of 2-unsubstituted pyrazol-3-one 552 with 1-chloropropane-1,2-dione 1 -(TV-phenylhydrazone) 553 requires heating in ethanol containing triethylamine to give pyrazol-3-one 554 (84BCJ1650). Under similar conditions 

Tetraglucose 565 was derivatised with pyrazol-3-one 564 by dissolving it in methanol containing sodium hydroxide and heating in a sealed tube at 70 °C. 

4-Dihydropyrazol-3-ones bearing a hydroxyethyl side-chain at C4 can undergo intramolecular substitution of the hydroxyl group at the same position to give a spiropyrazol-3-one. On the other hand, the hydroxyethyl group of 1,2-dihydropyrazol-3-ones was converted into a bromoethyl group before cyclization. 

3- nitrothiophens, which in addition could be greater or smaller than unity depending upon the leaving group. As in most aromatic nucleophilic substitutions, the absence of element effect was observed. 

Meisenheimer-type adducts have been obtained from the reaction of 2-methoxy-3-nitrothiophen and 2-methoxy-3,5-dinitrothiophen with sodium methoxide, An interesting adduct in which the methoxy-group is attached to the 5-carbon was observed with 2-nitro-3-methoxythiophen. The n.m.r. spectra of the complexes were analysed.The specific rate 

Guanti, C. Dell Erba, and D. Spinelli,/. Heterocyclic Chem., 1970, 7, 1333. 

The preparative usefulness of the copper-catalysed nucleophilic substitution in the thiophen series is evident from the preparation of the four 

Quinolines and isoquinolines are susceptible to addition of nucleophiles only at the heterocyclic ring. In quinoline, there is only one a- and one y-position prone for attack, whereas in isoquinoline, two a-type positions in which 1-position is much more favored due to the inability of nitrogen atom to delocalize a negative charge. In general, the nucleophilic attack is easier in these bicyclic systems in comparison to pyridine compounds because of the associated resonance stabilization offered by the fused-benzene ring. 

Both quinolines and isoquinolines can be hydroxylated by heating them with potassium hydroxide, forming the tautomeric quinolin-2-one and isoquinolin-l-one derivatives. The formation of these adducts can be regarded as an SnAr process that proceeds with the evolution of hydrogen.  

Similar to that of pyridine, the Chichibabin amination on quinoline and isoquinoline proceeds with alkali metal amides in liquid ammonia. In accordance to that, the reaction of quinoline with liquid ammonia initially forms a complex, which allows amide anion to add to the heterocyclic core of quinoline and isoquinoline bicycle, obtaining 2- or 4-aminoquinolines and 1-aminoisoquinolines, respectively, in good yields.  

The same logic can be followed on the nucleophilic attack of alkyl or aryl groups on C2 position of quinoline and Cl position of isoquinoline cores by organometalic species (lithium or Grignard reagents). The reaction seems to proceed in two steps as this is demonstrated in the alkylation of isoquinolile below. Addition at the Cl position gives a dehydroisoquinoline-A-lithio derivatives, which can be hydrolyzed to furnish an isolable 1-substituted 1,2-dihydroisoquinoline. It was followed by an oxidation process to yield the full aromatized product.  

In addition to the nucleophilic substitution of hydride atom from quinolines and isoquinolines, a reaction of high value for introduction of variety of substituents is the nucleophilic displacement of leaving groups on the heterocycle. As an example, 4-chloro-8-trifluoromethylquinoline reacts in a nucleophilic displacement of chlorine atom with methyl anthranilate, to provide the precursor of NS AID antihacterial flocatfenine.  

Haloalkanes contain an electrophilic carbon atom, which may react with nucleophiles— substances that contain an unshared electron pair. The nucleophile can be an anion, such as hydroxide ( OH), or a neutral species, such as ammonia (tNHs). In this process, which we call nucleophilic substitution, the reagent attacks the haloalkane and replaces the halide. A great many species are transformed in this way, particularly in solution. The reaction occurs widely in nature and can be controlled effectively even on an industrial scale. Let us see how it works in detail. 

The nucleophilic substitution of a haloalkane is described by either of two general equations. Recall (Section 2-2) that the curved arrows denote electron-pair movement. 

Nucleophilic substitution changes the functional group in a molecule. A great many nucleophiles are available to participate in this process therefore, a wide variety of new molecules is accessible through substitution. Note that Table 6-3 depicts only methyl, primary, and secondary halides. In Chapter 7 we shall see that tertiary substrates behave differently toward these 

Reaction number Substrate Nucleophile Product Leaving group 

Note Remember that nucleophiles are red, electrophiles Anionic nucleophiles give neutral products (Reactions 1 (Reactions 6 and 7). are blue, and leaving groups are green. -5). Neutral nucleophiles give salts as products  

The ionization mechanism has several distinguishing features. The ionization step is rate determining and the reaction exhibits first-order kinetics, with the rate of decomposition of the reactant being independent of the concentration and identity of the nucleophile. The symbol assigned to this mechanism is Sjyl, for substitution, nucleophilic, unimolecular. 

According to the ionization mechanism, if the same carbocation can be generated from more than one precursor, its subsequent reactions should be independent of its origin. But, as in the case of stereochemistry, this expectation must be tempered by the fact that ionization initially produces an ion pair. If the subsequent reaction takes place from this ion pair, rather than from the completely dissociated and symmetrically solvated ion, the leaving group can influence the outcome of the reaction. 

Front-side approach is disfavored because the density of the a orbital is less in the region between the carbon and the leaving group and, as there is a nodal surface between the atoms, a front-side approach would involve both a bonding and an antibonding interaction with the a orbital. 

The direct displacement (S/ 2) mechanism has both kinetic and stereochemical consequences. reactions exhibit second-order kinetics—first order in both reactant and nucleophile. Because the nucleophile is intimately involved in the rate-determining step, not only does the rate depend on its concentration, but the nature of the nucleophile is very important in determining the rate of the reaction. This is in sharp contrast to the ionization mechanism, in which the identity and concentration of the nucleophile do not affect the rate of the reaction. 

Owing to the fact that the degree of coordination increases at the reacting carbon atom, the rates of S 2 reactions are very sensitive to the steric bulk of the substituents. 

Reaction mechanisms for hydrolysis can be classified according to the type of reaction center involved. The primary distinction is made between reaction at saturated and unsaturated centers. With respect to carbon-centered functional groups, which will be the primary focus of this chapter, hydrolysis involves reactions at sp (saturated) or sp (unsaturated) hybridized carbons. Nucleophilic reactions at sp carbons are termed nucleophilic substitution (2.7). The reaction at sp carbons is termed nucleophilic addition-elimination or acyl substitution (2.8). 

Because both the nucleophile, Y , and the leaving group, X , are Lewis bases, these are examples of Lewis acid-base reactions in which one Lewis base replaces another in the Lewis acid-base adduct (Jensen, 1978). 

The limiting cases of nucleophilic substitution have been described as the ionization mechanism (SnI, substitution-nucleophilic-unimolecular) and the direct displacement mechanism (8 2, substitution-nucleophilic-bimolecular Gleave et al., 1935). The S l and Sn2 mechanisms describe the extremes in nucleophilic substitution reactions. Pure SnI and Sn2 reaction mechanisms, however, are rarely observed. More often a mix of these reaction mechanisms are occurring simultaneously. 

The SnI mechanism begins by a rate-determining heterolytic dissociation of the substrate to an sp hybridized carbocation (commonly referred to as a carbonium ion) and the leaving group (2.9)  

Trost and Scanlan reported a Pd-catalyzed condensation of a vinyl epoxide 75 and an allyl sulfone 76 in the presence of dppf under neutral conditions [231]. This alkylation allows a room temperature entry to a basic indolizidine ring system as a step towards the synthesis of (+)-aj//o-Pumiliotoxin 339B [232], The modification of allylic alkylations by condensation of a diene 77 with a pronucleophile 78 also leads to C-C bond formation at the allylic position in both 1 1 (79 and 80) and 2 1 (81 and 82) products [233]. Reactions between ketene silyl acetals 83 with allyl 

Ingold, Structure and Mechanism in Organic Chemistry, 2nd ed., Cornell University Press, Ithaca, New York, 1969. 

The Limiting Cases—Substitution by the Ionization (SktI) Mechanism 

The ionization mechanism for nucleophilic substitution proceeds by rate-determining heterolytic dissociation of the reactant to a tricoordinate carbocation (also sometimes referred to as a carbonium ion or carbenium ion f and the leaving group. This dissociation is followed by rapid combination of the highly electrophilic carbocation with a Lewis base (nucleophile) present in the medium. A two-dimensional potential energy diagram representing this process for a neutral reactant and anionic nucleophile is shown in Fig. 

This mechanism has several characteristic features. Because the ionization step is rate-determining, the reaction will exhibit first-order kinetics, with the rate of decom- 

TIricooRlinate caibocations are fiequendy called carbonium ions. The terms methyl cation, butyl cation, etc., are used to describe the c rTesixiiulir.ji tricoordinate cations. Chemical Abstracts uses as specific names methylium, ethyUum, propylium. We will use carbocation as a generic term for trivalent carbon cations. 

When pyridine is reacted with nucleophiles the attack occurs preferentially at C-2(6) and/or at C-4, as predicted by the resonance descrip- 

An intermediate formed through attack at C-3(5) would not permit the negative charge to be 

Q Outline a synthesis of 2-acetoxy-4-methoxypyridine from pyridine. 

This occurs because 3-pyridyne (3,4-didehydropyridine) is formed by an alternative mechanism is the ElcB process [elimination (first order) from the conjugate base], SowM 3-Pyridyne then adds ammonia the addition is not regiospecific and two second step, amino derivatives are formed. 

The reaction of organolithium compounds with pyridines, discovered initially by Ziegler and Zeiser228 has been investigated much 

Lukes and J. Kuthan, Coll. Czech. Chem. Commuti. 26, 1422 and 1845 (1961). 

Kuthan, E. Janeckova, and M. Havel. Coll. Czech. Chem. Commun. 29, 143 (1964). 

The reaction of a lithium alkyl or aryl with dry pyridine involves the formation of a dihydro derivative (103) which, on heating or on being oxidized with molecular oxygen in the cold, furnishes the 2-substituted pyridine 104. Alternatively, 103 may be treated with water to give the 1,2-dihydro derivative which is converted to 104 by oxidation with picric acid (in which case the picrate of 104 is the product isolated) or with chloranil.229 No 4-phenylpyridine could be detected by gas chromatography in the reaction with phenyllithium.230 Support for 

Reactions op Alkyl- and Aryllithium Derivatives with Some 2- or 4-Substituted Pyridines 

When we discussed elimination reactions in Chapter 5, we learned that a Lewis base can react with an alkyl halide to form an alkene. hi the present chapter, you will find that the same kinds of reactants can also undergo a different reaction, one in which the Lewis base acts as a nucleophile to substitute for the halide substituent on carbon. 

We first encountered nucleophihc substitution in Chapter 4, in the reaction of alcohols with hydrogen halides to form alkyl halides. Now we ll see how alkyl halides can themselves be converted to other classes of organic compounds by nucleophilic substitution. 

This chapter has a mechanistic emphasis designed to achieve a practical result. By understanding the mechanisms by which alkyl halides undergo nucleophilic substitution, we can choose experimental conditions best suited to carrying out a particular functional group transformation. The difference between a successful reaction that leads cleanly to a desired product and one that fails is often a subtle one. Mechanistic analysis helps us to appreciate these subtleties and use them to our advantage. 

Nucleophilic substitution reactions of alkyl halides are related to elimination reactions in that the halogen acts as a leaving group on carbon and is lost as an anion. The carbon-halogen bond of the alkyl halide is broken heterolytically the pair of electrons in that bond are lost with the leaving group. 

The carbon-halogen bond in an aUcyl halide is polar 

These four types of reactions are by far the most common, although others such as anionic substrate + anionic nucleophile can occur if sufficiently reactive reactants are chosen. The factors that influence the reactivity of nucleophiles and substrates will be among the topics considered in this chapter. 

The ionization mechanism for nucleophilic substitution proceeds by ratedetermining heterolytic dissociation of the substrate to a tricoordinate carbocation 

The consequences of this mechanism are evident. The reaction will exhibit 

Tricoordinate carbocations are customarily called carbonium ions for a clear discussion of terminology and a suggestion favoring the view that the term carbonium ion be reserved for pentacoordinate carbocations, with tricoordinate carbocations being referred to as carbenium ions, see G. A. Olah, J. Am. Chem. Soc. 94, 808 (1972). 

Application of Hammond s postulate indicates that the transition state should resemble the product of the first step, the carbocation intermediate. Ionization will be facilitated by factors that either lower the energy of the carbocation or raise the energy of the reactant. The rate of ionization will depend primarily on how reactant structure and solvent ionizing power affect these energies. 

SECTION 5.1. THE LIMITING CASES— SUBSTITUTION BY THE IONIZATION (SnU MECHANISM 

Tricoordinate carbocations are customarily called carbonium ions for a clear discussion of terminology and a suggestion favoring the view that the term carbonium ion be reserved for pentacoor-dinate carbocations, with tricoordinate carbocations being referred to as carbenium ions, see G. A. Olah, J. Am. Chem. Soc. 94, 808 (1972). Current practice uses both terms and also terms such as methyl cation and butyl cation to describe carbonium ions. Chemical Abstracts uses as specific names methylium, ethylium, etc. We will use carbonium ion as a generic term for trivalent carbocations. We will use methyl cation, ethyl cation, etc., when referring to specific ions. 

In the first step, glycine Schiffbase 1 reacts with the inorganic base at the interface of two phases to give the metal enolate 2, which remains at the interface due to its highly polar character. The metal enolate 2 then exchanges the cation to provide onium enolate 3. The sufficiently lipophilic 3 then moves into the organic phase to react with alkyl halide. After the reaction, onium halide (Q X ) is regenerated and enters the next catalytic cycle. The key issue to be considered here is the possibility of product racemization and dialkylation. In this example, the basicity 

The phase-transfer-catalyzed asymmetric conjugate additions [19] and Mannich reactions [20] are other typical examples that fall into this category. 

spectra of the Meisenheimer complex of 2-nitrothiophen and 2-nitrofuran with methoxide ion have been compared. Evidence has been obtained for the formation of spiro-Meisenheimer compounds (130) and (131) 

4- di-(2-thienyl)buta-l,3-diyne. It was demonstrated that the main, and probably radicaloid, reaction patterns of di-(3-thienyl)iodonium chloride in the presence of certain nucleophiles, such as cyanide ion, methoxide ion, and piperidine, can be almost completely altered by the addition of copper salts. Instead of reduction to thiophen and iodothiophen, or polymerization, arylation of the nucleophiles occurred, which led to 3-cyano-3-methoxy- or 3-piperidino-thiophen as the main product in addition to 3-iodothiophen.  

5- dibromothiophen with butyl-lithium or ethylmagnesium bromide, release of steric strain caused an increase in the reactivity of the 2-position over that of the 5-position on going from 2,5-dibromo-3-methyl- to 2,5-dibromo-3-t-butyl- 

4-bromo-3-thienyl-lithium or 4-bromo-3-selenienyl-lithium with DMF, undergoes metallation with butyl-lithium in the 2-position ortho to the protected aldehyde group. This was utilized for the synthesis of jS-bromo-substituted thieno-[2,3-/)]thiophen and seleno[2,3-6]thiophen derivatives. Thienyl-lithium derivatives were used for the synthesis of a variety of deuteriated thiophen aldehydes needed for conformational studies, and for the fixed conformation ester  

Clarke, S. McNamara, and O. Meth-Cohn, Tetrahedron Letters, 1974, 2373, 

Unlike nucleophilic substitution reactions, which generate stable onium haUde after the reaction, nucleophilic additions to electrophilic C=X double bonds (X = C, N, O) provide rather basic onium anion species as an initial product If the anion is sufficiently stable under the reaction conditions, the onium anion wiU then exchange the counter ion for the other metal carbanion at the interface to regenerate the reactive onium carbanion Q R . In another scenario, the basic onium anion may abstract the acidic hydrogen atom of the other substrate to provide Q R directly. Such a reaction system ideally requires only a catalytic amount of the base although, in general, a substoichiometric or excess amount of the base is used to lead the reaction to completion. An additional feature of this system is the substantial possibility of a retro-process at the crucial asymmetric induction step, which might be problematic in some cases. 

---

Nucleophilic substitution of benzene itself is not possible but the halogeno derivatives undergo nucleophilic displacement or elimination reactions (see arynes). Substituents located in the 1,2 positions are called ortho- 1,3 meta- and 1,4 para-. 

These reactions follow first-order kinetics and proceed with racemisalion if the reaction site is an optically active centre. For alkyl halides nucleophilic substitution proceeds easily primary halides favour Sn2 mechanisms and tertiary halides favour S 1 mechanisms. Aryl halides undergo nucleophilic substitution with difficulty and sometimes involve aryne intermediates. 

Hase W L 1994 Simulations of gas-phase chemical reactions applications to S j2 nucleophilic substitution Science 266 998-1002... 

The higjily water-soluble dienophiles 2.4f and2.4g have been synthesised as outlined in Scheme 2.5. Both compounds were prepared from p-(bromomethyl)benzaldehyde (2.8) which was synthesised by reducing p-(bromomethyl)benzonitrile (2.7) with diisobutyl aluminium hydride following a literature procedure2.4f was obtained in two steps by conversion of 2.8 to the corresponding sodium sulfonate (2.9), followed by an aldol reaction with 2-acetylpyridine. In the preparation of 2.4g the sequence of steps had to be reversed Here, the aldol condensation of 2.8 with 2-acetylpyridine was followed by nucleophilic substitution of the bromide of 2.10 by trimethylamine. Attempts to prepare 2.4f from 2.10 by treatment with sodium sulfite failed, due to decomposition of 2.10 under the conditions required for the substitution by sulfite anion. 

The Peterson reaction has two more advantages over the Wittig reaction 1. it is sometimes less vulnerable to sterical hindrance, and 2. groups, which are susceptible to nucleophilic substitution, are not attacked by silylated carbanions. The introduction of a methylene group into a sterically hindered ketone (R.K. Boeckman, Jr., 1973) and the syntheses of olefins with sulfur, selenium, silicon, or tin substituents (D. Seebach, 1973 B.T. Grdbel, 1974, 1977) illustrate useful applications. The reaction is, however, more limited and time consuming than the Wittig reaction, since metallated silicon derivatives are difficult to synthesize and their reactions are rarely stereoselective (T.H. Chan, 1974 ... 

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. 

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. 

With higher alkenes, three kinds of products, namely alkenyl acetates, allylic acetates and dioxygenated products are obtained[142]. The reaction of propylene gives two propenyl acetates (119 and 120) and allyl acetate (121) by the nucleophilic substitution and allylic oxidation. The chemoselective formation of allyl acetate takes place by the gas-phase reaction with the supported Pd(II) and Cu(II) catalyst. Allyl acetate (121) is produced commercially by this method[143]. Methallyl acetate (122) and 2-methylene-1,3-diacetoxypropane (123) are obtained in good yields by the gas-phase oxidation of isobutylene with the supported Pd catalyst[144]. 

As is broadly true for aromatic compounds, the a- or benzylic position of alkyl substituents exhibits special reactivity. This includes susceptibility to radical reactions, because of the. stabilization provided the radical intermediates. In indole derivatives, the reactivity of a-substituents towards nucleophilic substitution is greatly enhanced by participation of the indole nitrogen. This effect is strongest at C3, but is also present at C2 and to some extent in the carbocyclic ring. The effect is enhanced by N-deprotonation. 

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. 

Chapter 12. Modification of 3-Alkyl Substituents by Nucleophilic Substitution. 119... 

Piperazinothiazoies (2) were obtained by such a replacement reaction, Cu powder being used as catalyst (25. 26). 2-Piperidinothiazoles are obtained in a similar way (Scheme 2) (27). This catalytic reaction has been postulated in the case of benzene derivatives as a nucleophilic substitution on the copper-complexed halide in which the halogen possesses a positive character by coordination (29). For heterocyclic compounds the coordination probably occurs on the ring nitrogen. 

Charge diagrams suggest that the 2-amino-5-halothiazoles are less sensitive to nucleophilic attack on 5-position than their thiazole counterpart. Recent kinetic data on this reactivity however, show, that this expectation is not fulfilled (67) the ratio fc.. bron.c.-2-am.noih.azoie/ -biomoth.azoie O"" (reaction with sodium methoxide) emphasizes the very unusual amino activation to nucleophilic substitution. The reason of this activation could lie in the protomeric equilibrium, the reactive species being either under protomeric form 2 or 3 (General Introduction to Protomeric Thiazoles). The reactivity of halothiazoles should, however, be reinvestigated under the point of view of the mechanism (1690). 

Aromatic nucleophilic substitution of 2- or 5-halogenotltia20les (146 and 148) by sulfinate affoiMs an alternative method of preparation of sulfones (147 and 149) (Scheme 76) (170, 354-356). 

Nucleophilic substitution of the 5-halo substituent on a thiazole ring by a thiocyanato group (348, 362, 370-376) or a thiouronium group (364, 377) affords the thiocyanato and thiouronium precursors."... 

With a carboxy group on the alkyl chain of the alkylthio substituent. C-4 may be involved in an intramolecular nucleophilic substitution to give 159 (Scheme 84). 

Table 1-4 gives some calculated reactivity indices free valence or Wheland atomic localization energies for radical, electrophilic, or nucleophilic substitution. For each set of data the order of decreasing reactivity is indicated. In practice this order is more reliable than the absolute values of the reactivity indices themselves. 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

Arylamino-2-chloroprop-2- enoic esters (72) obtained from 2-chloroaceto acetic ester (71) and arylamines, react with thiourea to yidd substituted 2-aminothiazoles (73), probably by initial nucleophilic substitution of the chloro atom of 72, followed by cyclization with loss of aniline (Scheme 33) (729). 

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