Substitution reactions,

Substitution is facilitated for a substituent attached to an a-carbon in 7i-allyl complexes, equation (6-33). This activation toward substitution has 

The aromatic character of complex [6-19] is readily rationalized by the conventional mechanism for electrophilic substitution involving a Ti-ally-iron tricarbonyl cationic complex [6-20] shown in equation (6-35). 

It is postulated that since analogous stable 7c-allyl-iron tricarbonyl cationic salts have been isolated, [6-20] may be expected to provide a low-energy pathway for the substitution process. 

In a substitution reaction, an atom or group of atoms (Y) replaces another atom or group of atoms (L) in some molecular entity (RL). In shorthand notation. 

Perspectives on Structure and Mechanism in Organic Chemistry, Second Edition By Felix A. Carroll Copyright 2010 John WUey Sons, Inc. 

It is convenient to categorize reactions with concise descriptive labels. For substitution reactions we often use the notation SxM, in which the letter S indicates a substitution reaction. The subscript x indicates something of the mechanism, such as N for nucleophilic or E for electrophilic. M usually indicates the molecularity of the reaction, the nature of the reacting species, or additional information. The most familiar terms for substitution reactions are SnI (for substitution nucleophilic unimolecular ), as shown in equation 8.4, 

These terms were suggested by Ingold and are familiar to all organic chemists. 

Typically, the kinetics of simple aliphatic substitutions are overall second order for 5 2 reactions and overall first order for SnI reactions. That is, an Sn2 reaction between Y and R-L leads to the rate equation 

The saturated hydrocarbons can react without a big disruption of the molecular struc-mre only by displacement, or substitution of one atom jbr another. At room temperamre, chlorine and bromine react very slowly with saturated straight-chain hydrocarbons. At higher temperatures, or in the presence of sunhght or other sources of ultraviolet light, H atoms in the hydrocarbon can be replaced easily by halogen atoms. These substitution reactions are called halc enation reactions. 

Unless olheiwise noted, all content on this page is Cengage Learning. 

Many organic reactions produce more than a single product. For example, the chlorination of CH4 may produce several other products in addition to CH3CI, as the following equations show. 

When a hydrocarbon has more than one C atom, its reaction with CI2 is more complex. The first step in the chlorination of ethane gives the product that contains one Cl atom per molecule. 

Substitution reactions usually occur with saturated molecules. A typical case is the reaction of chlorine and methane in which the hydrogen atoms of methane are replaced by chlorine in sequence—for example, 

For long chains of these reactions, each step must be exothermic. Typical examples include Cl2 in carboxylic acids, and BrCCl3 in alkyl aromatics. The products are variable substitution and side chain substitution compounds, respectively. 

Radiation-induced substitution reactions have been reviewed by Wilson (1972) with examples of nitration, nitrosation, sulfochlorination, and others. These generally proceed by a free-radical mechanism. The free radicals are generated by the action of radiation on the reagent, which is present in large excess—for example, 

Chapter 11 Radiation Chemical Applications in Science and Industry 

Molecules containing two or more chlorine atoms may be produced by the reaction of chlorine atoms or molecules with products generated in the earlier stage of the process. Product yields depend on irradiation conditions and can reach as high as 105 pmol.J-1. With bromine and iodine, not all of the individual steps of the reaction are exothermic. Therefore, a sustained chain reaction is not expected, and the yields are low. 

Electrophilic substitution of the electron-deficient phenanthrolines requires drastic conditions and, as predicted by theory, occurs preferentially in the benzene ring and in positions / to the nitrogen atoms. Nucleophilic substitution would be expected to proceed at sites a and y to the nitrogen atoms. 

Nitration of 1,7-phenanthroline with fuming nitric acid and sulfuric acid at higher temperatures than used hitherto has improved252 the yield of 6-nitro-1,7-phenanthroline to 28%. 1,5-Diazafluorenone (3%) is a byproduct. Bromination of 1,7-phenanthroline in oleum gives either 6-bromo-l,7-phenanthroline or the 5,6-dibromo derivative, depending on reaction conditions.275 

Unlike 1,7-, 1,10-, and 4,7-phenanthrolines, which give nitrated products, the predominant product of the reaction of 1,8-phenanthroline (2) with mixed nitric and sulfuric acids is the 5,6-dione (59) (28%). Both the 5-nitro- (60) and 6-nitro-1,8-phenanthrolines (61) are formed, but in much lower yield ( 6-7%). 2,5-Diazafluorenone (62) is also present (6%).252 Bromination of 1,8-phenanthroline affords the 5- and 6-bromo derivatives and the 5,6-dibromo analog.275 

Reports of further studies of the nitration of 1,10-phenanthroline have appeared. Nitration with fuming nitric acid and concentrated sulfuric acid at 160°-170° gives 5-nitro-1,10-phenanthroline (75%) and 4,5-diazafluorenone (13%).252 

A much milder route to 5-nitro-1,10-phenanthroline involves nitration of the tris-phenanthroline complex of cobalt(III) which is readily nitrated in concentrated sulfuric acid at 80°. The free 5-nitro-l,10-phenanthroline can be isolated in 70% yield from the nitrated complex.276 

Eichenberger, P. Schmidt, and A. Rossi, Swiss Patent 373,753 (1964) 

Substitution reactions occur when two starting materials exchange groups to form two new products. 

The mechanism of these reactions can involve an initial electrophilic or nucleophilic attack on the key functional group. 

Substitution Reactions. As already mentioned (Eq. (3)) [39], bis-cyclometallated complexes of Pt(II) react very specifically with HCl, with elimination of one of the metallacyde-forming ligands and with formation of a chloro-bridged dimer. This is the method applied for the preparation of the bis-heteroleptic complexes. 

Exchange of one ligand in a metallacycle by another ligand has been observed in Pd(II) complexes dissolved in acidic solution [74]. Synthesis of a cyclometallic complex comprising six-membered metallacycles from species containing five-membered metallacycles has been achieved in this way. 

Substitution Reactions.—In contrast to benzo[6]thiophen, the thienothiophens undergo electrophilic aromatic substitution predominantly in the 

3- isomer, less than 0.04%, if any, was formed from the [3,2- ]-isomer. 

The thienothiophens appear to be more sensitive to acid than thiophen. 

Much polymerization, besides dibromination, was obtained earlier upon bromination with bromine in acetic acid. Bugge has, however, found that both thienothiophens are conveniently monobrominated by iV-bromo-succinimide (NBS) in acetic acid. Besides the 2-bromo-derivative, smaller amounts (9—15 mole %) of the 2,5-dibromo-derivative were obtained when equimolar amounts were used. With two equivalents of NBS, the 

5-dibromo-compounds were obtained in good yield. The crystalline monobromo-derivatives are unstable, in contrast to 2-bromothiophen, and decompose in a few hours at room temperature, but can be stored for weeks at — 15 °C. The tribromothiophens, which have been prepared before, could be reduced to the 3-bromo-derivatives by excess zinc in acetic acid. By the use of smaller amounts of zinc, 2,4-dibromothieno[2,3-6]thiophen could be obtained. 

Substitution reactions are reactions in which one ligand in a complex is replaced by another as shown by Eqs. (1) and (2), or in which one metal is replaced by another as in Eqs. (3) and (4). 

Both nucleophilic and electrophilic substitutions are common reactions of metal complexes. However most of the kinetic and mechanistic studies 

Any attempt to understand and predict something about the relative reactivities of metal complexes requires some knowledge about the nature and the energy of the metal-ligand bond. In recent years the valence bond theory as applied to these systems has been largely replaced, in chronological order, by the crystal field, the ligand field, and the molecular orbital theories. Detailed discussions of these theories are available elsewhere and only brief mention can be made here of some of the necessary fundamentals. 

Restricting ourselves to a six-coordinated system and to the valence bond theory and crystal field theory, it is possible to illustrate the bonding in complexes and to designate the nomenclature using [CoFe] and [Co(NH3)e] + as examples. It is first necessary to know that [CoFs] is paramagnetic with four unpaired electrons, whereas [Co(NH3) ] + is diamagnetic. On the basis of the valence bond theory the electronic structures are designated as ( 5) or cPsp (6) hybridizations. 

Thus [CoFg3 is called an outer-orbital (uses nd orbitals) or a spin-free or high-spin (electrons are not paired) complex, and [ Co(NHs)6] is called an inner-orbital (uses (w — l)d orbitals) or a spin-paired or low-spin (electrons are paired) complex. 

Substitution Reactions.—The reactivities of thieno[3,2-b]thiophen and thieno[2,3-b]thiophen, relative to thiophen, in electrophilic formylation, 

5-Diformylthieno[2,3-b]thiophen prepared by metallation of thienot2,3-b]-thiophen with excess butyl-lithium and DMF has been used as a building-block for heterohelicene syntheses.  

Non-classical Thlenothiophens.—Detailed papers on the synthesis and chemical reactions of 1,3-disubstituted thieno[3,4-c]thiophens, e.g. (249) and (250), and on the stable tetraphenyl derivative (251), have appeared.  

Compound (251) is non-polar, gives no e.s.r. signal, and thus appears to contain sulphur atoms with considerable quadricovalent character. An X-ray study indicates that the four phenyl groups are not coplanar with the ring system. A convenient synthesis of 3,4-dibenzoyl-2,5-diphenyl-thiophen (252), a useful starting material for (251), has been described in the 

Reaction of phenylsydnone (25Q with dibenzoylacetylene gave (257), which again could be converted into (258) by reaction with P2S5 in pyridine. The brick-red (258) easily underwent cycloadditions with acetylenic and 

In substitution reactions, one atom (or group of atoms) is replaced by another atom (or group of atoms). The atom or group that is replaced is not utilised in the final product. So the substitution reaction is less atom-economical than rearrangement or addition reactions. Consider the substitution reaction of ethyl propionate with methyl amine 

In this reaction, the leaving group (OC2H3) is not utilised in the formed amide. Also, one hydrogen atom of the amine is not utilised. The remaining atoms of the reactants are incorporated into the final product. 

The total of atomic weights of the atoms in reactants that are utilised is 

106 g/mole, while the total molecular weight including the reagent used is 133.189 g/mole (see table). Thus, a molecular weight of46.069 g/mole remains unutilised in the reaction. 

Many substitution reactions are carried out on polymers in order to replace atoms in the backbones or in the pendant groups with other atoms or groups of atoms. These reactions do not differ much from those of the small molecules. 

This section is concerned with reactions of the type  

Thermodynamically, the feasibility of such a reaction will depend on the 

The bimolecular rate-determining step implies a second-order reaction. The intermediate can often be identified (e.g. spectroscopically) or even isolated and characterised in the case of a free radical, it can sometimes be trapped by reagents which quickly bind such species to give a readily-identifiable product. 

A heterolytic rupture will, in the case of an ordinary covalent bond, lead to formation of a cation and an anion in the case of a coordinate bond, the ligand simply departs along with the electron pair it contributed to form the bond. A dissociative mechanism exhibits first-order kinetics its rate is independent of the concentration of the incoming group Z. The intermediate EX in the overall reaction  

An intermediate situation between the A and D extremes is an interchange (/) mechanism. Here, the breaking of the E-Y bond and the formation of the E-Z bond occur simultaneously as a concerted process at no time is there an intermediate with both a fully-formed E-Y and an E-Z bond. The transition state is a complex which can be described as Y... EX ... Z. Like the A mechanism, the kinetics are second order, but the intermediate (or activated complex) has no real existence as a static entity in the reaction mixture unlike the intermediate in the A mechanism, there is no energy barrier to the breakdown of Y... EX ... Z, which appears as a maximum on the profile of energy 

Each year it is evident that photosubstitution processes of aromatic systems cannot readily be classified and again the order of reviewing the literature in this Section is largely arbitrary. Further details and applications have appeared of two rules which were first proposed in 1984 to rationalize the regiochemistry of 

As well as analyzing various substitution processes by these rules, the proposers report support for the second of the rules from the irradiation of 4-nitronaphthyl ethers (98) which yields 

Photonucleophilic substitution of fluoro- and chloro-anisoles has been the subject of three reports within the year. Cornelisse and co-workers have studied the photocyanation and photohydrolysis of 4-fluoro- and chloro-anisoles by laser spectroscopy and report that the initial step of the reaction involves formation of a triplet state transient complex composed of a ground state and an excited state aromatic molecule. Only in the presence of water does the complex yield radical ions and it is this process which determines the product quantum yield. The radical cation then reacts with the nucleophile to give a neutral radical which yields the substituted arene in a single step. Liu and Weiss report on anomalous effects during photonucleophilic aromatic substitution of 2- and 4-fluoroanisoles and also on the photo- 

The photoreactions of fluoro- and methoxy- benzenes in the presence of amines had been earlier described but these substitution and addition processes have been re-examined with diethylamine 

The photoreactions of dicyanobenzenes with allyl silanes which 74 

Whereas uncatalyzed substitution reactions of organozinc compounds are limited to very reactive electrophiles, metal-transmetallated organozinc compounds are able to perform substitution reactions on various electrophiles. In the case of conjugated electrophiles, these zinc copper reagents can follow a Sn2 or Sn2 mechanism. 

Ligand substitution is an important step in many reactions of coordination complexes. These reactions have been the subject of extensive mechanistic and kinetic studies. 

Many examples of photosubstitution reactions in aromatic systems are reported, and it is not easy to group the reactions on a mechanistic basis (in part because 

Electrophilic substitution in excited-state aromatics is the subject of only one report, concerned with a photophysical investigation of hydrogen-deuterium exchange in 1-methoxynaphthalene.  

Irradiation of 2-fluoropyridine (74 R = F) with t-butylamine or diethylamine gives (di)alkylaminopyridine as the sole product, formed by nucleophilic photo-substitution. With triethylamine a more complex mixture of products is formed. Pyridine itself (74 R = H) reacts with diethylamine, triethylamine, or diethyl ether to give 2- and 4-substituted pyridines that reflect attack on the a-methylene group in the aliphatic component this process involves a formal hydrogen-abstraction step from the activated CH2 group by an excited-state aromatic. A full report has now appeared of the reactions of alkenes with 3-chlorotetrafluoro-pyridine (75), and also with 3,5-dichloro-2,4,6-trifluoropyridine, where insertion 

Tobita and H. Shizuka, Koen Yoshishu Bunshi Kozo Sogo Toronkai, 1979, 228 Chem. Abstr., 1980, 93, 185 503). 

On irradiation, amines readily replace a hydrogen (or halogen) in a wide range of nitroindazoles e.g., 76), and in a few cases ethanol similarly gives rise to 

The photochemical nucleophile-olefin combination, aromatic substitution (photo-NOCAS) reaction between methanol, 7-methyl-3-methyleneocta-1,6-diene and 1,4-dicyanobenzene gives the five 1 1 1 adducts cw-2-(4-cya-nophenyl)-4-( 1 -methoxy-1 -methylethyl)-1 -methylenecyclohexane, trans-2-(4  

4-methoxybenzyl(trimethyl)silane leads to the formation of benzylated succinic acid.  

Concentration-dependent isotope effects (lEs) have been measured in the competitive photocyanation of naphthalene and perdeuterionaphthalene, and have been shown to be influenced by the concentration of the reagents naphthalene, cyanide and oxygen. Together with semiempirical PM3 calculations and other measurements, the variation of the IE with naphthalene concentration is suggested to be ascribable to excited state equilibration a detailed mechanism to explain the observed lEs is proposed. 

The photo-Reimer-Tiemann reaction of phenols with chloroform in the presence of 3-cyclodextrin has been reported to produce 4-hydroxy-benzaldehydes with high selectivity.  

The nitration of benzene is an example of an electrophilic substitution reaction  

Nitric acid and sulfuric acid react to produce the nitronium ion ( N02), which acts as the electnyhile  

The positively charged nitronium ion is attracted to the electron-rich pi bonds of the benzene ring. A bond forms between one of the carbon atoms and the nitronium ion, breaking one of benzene s pi bonds  

Finally, the electrons in the C—H bond move to the ring, restoring the original pi bond, and the hydrogen atom leaves as a proton, H  

When necessary, one additional step can convert the —NOi group into the —NH2 group . NO2  

Student Annotation The C atom in methyl bromide bears a partial positive charge because it is bonded to the somewhat more electronegative bromine atom [Mt Section 8.4], 

Student Annotation Digestion of proteins also begins with a nucleophilic substitution reaction. 

Much of the interest in photosubstitution reactions originates in their potential application to photoaffinity labelling. An example has been publlshed of the use of 2-fluoro-4-nltroanlsole for this purpose in which the methoxy group is displaced by the 

Quantiim yields have been determined for displacement of alkoxy groups in 3-alkoxynitrobenzenes by hydroxide ion in aqueous and micelle solutions to give 3-nitrophenol. The quantvun yields are higher in the micellar medium. The photolysis of 3-nitrophenol itself has been studied in aqueous solution.The quantum yields for disappearance are very low (in the order of 10 ) and numerous products are formed which include resorcinol, nitroresorcinol and nitrocatechols. 

A chain (Sj, ) mechanism is proposed for the light initiated substitution of halogen by sulphite in halo-substituted naphthols. The reaction is initiated by electron transfer from sulphite to an excited sensitiser dye. The sulphite anion radical produced then attacks the halonaphthol loss of halide from this species to give the product is coupled with electron transfer from a second sulphite, so propagating the chain. 

With alkenes in polar solvents 2,4-dicyanopyrldlne reacts similarly to give products of the type (97) however if the reaction is performed in less polar solvents then proton transfer in the initially produced radical ion pair apparently competes to produce an allyl radical and pyridyl radical. These couple and eventually give (98). With euaine donors coupling of the radical ion pair results in the isolation of (99) and (100) 

Photochemical cyanation of nitroimidazoles (106) to give cyanoimidazoles (107) has been reported as a synthetically useful procedure. 

Even back in 1912, Werner was keenly aware of the need to understand metal complex substitution. Stereochemical changes [e.g., cis-trans conversions, equation (1.2)] in cobalt(III) complexes were critical to the development of his coordination theory and he sought to understand how these occurred. 

There are many other reasons why coordination chemists study substitution kinetics, one of the most common being that substitution provides a route for the synthesis of new coordination complexes. The synthesis of [Co(en)3]3+ from Werner s purpureo complex, [Co(NH3)5C1]+, by ethylenediamine substitution, equation (1.3), and the synthesis of [Cu(NH3)4]2+ by NH3 substitution of the aqua complex, [Cu(H20)4]2+, equation (1.4), are two notable examples. 

The reaction in equation (1.3) involving cobalt(III) is very slow at room temperature (the reaction must be heated to take place), while that in equation (1.4) involving copper(II) is rapid at room temperature, despite similar NH3 group ligation. The substitution rates depend markedly on the nature of the metal ion. 

The D and A pathways proceed through intermediates of reduced and increased coordination numbers, respectively. The I mechanisms are characterized by the lack of an intermediate with a modified metal ion coordination number in the reaction. When bond breaking is more important than bond making the mechanism is Id the transition state has a reduced coordination number. In an Ia mechanism bond making is more important than bond breaking the transition state has an increased coordination number. 

The importance of substitution reactions cannot be overstated. Systematic investigations of coordination compound substitution kinetics, and mechanisms shed light on the electronic structure of compounds and on their interactions. Although formally taken up in Chapter 4, substitution is encountered in all chapters of this book. 

Solvent exchange processes are the most fundamental substitution reactions that characterize the lability and reaction mechanism of a metal center within a coordination geometry. For these reactions the interpretation of the volume of activation becomes rather straightforward since these reactions do not involve major changes in solvation due to changes in dipole moments and electrostriction, which can in 

Density functional theory has also been applied successfully to describe the solvent exchange mechanism for aquated Pd(II), Pt(II), and Zn(II) cations (1849 ). Our own work on aquated Zn(II) (19) was stimulated by our interest in the catalytic activity of such metal ions and by the absence of any solvent (water) exchange data for this cation. The optimized transition state structure clearly demonstrated the dissociative nature of the process in no way could a seventh water molecule be forced to enter the coordination sphere without the simultaneous dissociation of one of the six coordinated water molecules. More 

The pressure dependence of the forward and reverse reactions resulted in significantly positive volumes of activation (36), and the volume profile reported in Fig. 1 clearly demonstrates the dissociative nature of the substitution process. Such conclusions can more easily 

Reactants Transition state Products Reaction coordinate 

Contrary to many of the examples quoted so far, the observed volumes of activation may differ significantly from the expected and could lead to the suggestion of an unexpected mechanism. Basallote and co-workers (38) investigated the substitution of coordinated H2 by MeCN in THF in m s-[FeH(H2)(DPPE)2]+ (DPPE = l,2-bis(diphenyl-phosphino)ethane. The volumes of activation were measured under limiting conditions, i.e., where the observed rate constant is indepen- 

Within the year a wide range of photoreactions in which an aromatic residue undergoes change in substitution has been published. As previously, the diversity of the various processes makes any classification of the reactions unrealistic, and so their order of presentation here is somewhat arbitrary. Aromatic photosubstitution reactions have been reviewed by Parkanyi although the treatment is not extensive, the processes of free radical, electrophilic, and nucleophilic photoinduced substitutions of arenes are well covered.Arene photoreactions initiated by electron transfer with electron donors or acceptors are the subject of a review by Pac and Sakurai. The requirements for the efficient photogeneration of the ion radicals are considered and the synthetic utility of the photoreactions, which include reduction, cyanation, and amination, is discussed. 

There have been several recent investigations into the mechanism of photo-cyanation of aromatic hydrocarbons. The process with naphthalene, biphenyl, and phenanthrene has been subjected to a kinetic analysis the reactions in dry or aqueous methyl cyanide are shown to involve two transient species, the first of which is an ionic complex formed from a triplet excimer of the arene, or, in the presence of an electron acceptor, from a triplet exciplex. Reaction of the transient complex with the cyanide ion yields the radical ArHCN, and in aqueous methyl cyanide this second transient reacts with itself to produce dihydrocyano- and cyano-compounds. In dry methyl cyanide the radical species is oxidized to the cyano product. 

Photoreactions involving benzoic add are not common, but it is now reported that the arene moiety is susceptible to substitution in the presence of sodium hypochlorite in aqueous alkali at pH 12. At ratios of the order of 0.1 for [Q0 ] [PhC02 l, hydroxylation and chlorination of the aromatic ring occur simultaneously with ipso substitution at the carboxylate group (which yields phenol). At high relative concentrations of hypochlorite, the photo-products react further in the dark to yield polychlorinated derivatives. The reaction is discussed in terms of the initial steps being the generation of the active species 0( P), 0( D), O, and Cl from irradiation of C10 . 

Two reports this year describe the photochemistry of phenyl-lithium. The main products from irradiation in diethyl ether are biphenyl, ethylbenzene, phenetole, ethanol, and traces of o-terphenyl. In tetrahydrofuran solution the major product is biphenyl, and in the presence of hexene, 1-phenylhexane results.  

The photolability of nitrobenzenes has previously received comment, and reactions in the presence of carbon tetrachloride and diethanolamine have now been studied. In the former system the main products are chlorobenzene and hexachloroethane, with smaller amounts of CHCh, COCI2, and C2CI4. Nitrobenzene is photoreduced in the presence of the amine to give phenyl-hydroxylamine. The reaction is enhanced six-fold in the presence of 0.1 M benzophenone and is considered to proceed by way of hydrogen abstraction by the triplet nitro-arene from diethanolamine (which is degraded to glyoxal). 

Similar to the work described above, several publications on substitution reactions have dealt with solid-phase peptide synthesis. As already mentioned, these experiments are not addressed within this section and are summarized in Chapter 19. 

The successfully generated chalcones could be cleaved by treatment with tri-fluoroacetic acid or used for subsequent synthesis of pyrimidines [45]. Condensation of the polymer-bound chalcones with benzamidine hydrochloride under the action of microwave irradiation for 30 min furnished the corresponding pyrimidines in good yields after TFA-induced cleavage. 

After the reaction, the solid supported product was washed with N,N-dimethyl-formamide and dichloromethane and dried before being subjected to acylation. Coupling of the pyrene butanoic acid (PyBA) was again performed under the action of microwave irradiation at 80 °C for 10 min. 

In a comparable study glass was used as solid support - carbohydrates were attached to amino-derived glass slides. Significant rate enhancement was observed when this step was conducted under the action of microwave irradiation rather 

Subsequent cyclization and cleavage from the support were achieved by micro-wave heating with several hydrazines or hydroxylamines to afford the desired heterocyclic targets. The cellulose-bound aniline could be recycled by simple washing and re-used up to ten times without loss of efficiency or reduced purity of the resulting compounds. 

Several reports have appeared concerning photostimulated Srn1 reactions of aryl halides. In these processes substitution occurs via a chain mechanism as follows  

The photochemical step Is initiation of radical anion formation by electron transfer from the nucleophile to the aryl halide, one of the two being In the excited state. Thus amino acid substituted diaryl thioethers have been prepared In high 

Similarly, irradiation of benzene thiolate in the presence of halogen substituted 

N-arylation product (151). Similarly, irradiation of para-chloro cyanobenzene or pyridine in the presence of 2.6-di-ferf.-butyl phenolate yields the biaryi (152). The SrnI reaction has been reviewed. 

Blaryls are also commonly prepared by photolysis of aryl halides In the presence of arenes and several examples have appeared during the period of this report. Photolysis of lodothiophenes in the presence of thiophene gives 2.2 -bithienyls and this has been applied to the synthesis of several naturally occuring compounds. For example, irradiation of 2-iodothiophene-2-carbal-dehyde in the presence of 2-bromothiophene gives the bithienyl (153) In 99% yield. This is then converted Into a series of natural products In which the aldehyde and bromo functions of (153) are modified. Similarly. 

As the benzyl (a) carbon is the most reactive site on the propanoid side chain (Allan 1971), it is not surprising that many substitution reactions are documented as occurring at this position and at the vinylogous y-carbon atoms of p-hydroxycinnamyl alcohol units. The variety of substitution reactions occurring at the benzyl carbon atom has been thoroughly reviewed by Allan (1971). 

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 structure. Several representative substitution reactions are illustrated in Fig. 1.5. At moderate temperatures ( 100°C) and under mildly alkaline conditions, benzylic hydroxyl groups in phenolic units are converted to thiols by reaction with bisulfide (Q, Fig. 1.5). At higher temperatures and alkalinities, e.g., under kraft pulping conditions, the mercaptide group undergoes a series of transformations in which the sulfur is ultimately eliminated. 

In a reversal of the ether cleavage reactions described above, benzyl alcohols and ethers may be transformed to alkyl or aryl ethers via acid-catalyzed etherification or transetherification, respectively, by reaction with the appropriate alcohol or phenol (reaction R, Fig. 1.5). 

The conversion of a benzyl alcohol or ether to a sulfonic acid group is illustrated by reaction S in Fig. 1.5. This transformation is among the most important side chain modification reactions as it is central to the solubilization of 

As kinetic studies show (Chapter 14), many reactions in solution proceed through a reaction intermediate in which the solvent is coordinated. What may, on paper, appear to be an addition reaction may in fact be a ligand substitution reaction. 

As noted earlier, there is an experimental distinction between the substitution reactions of labile and inert complexes. The formation of labile complexes is virtually instantaneous upon mixing of the reactants, so that there are few practical difficulties in their preparation, but three points must be remembered. First, for classical, Werner-type, complexes it is found in practice that it is difficult to prepare such complexes with several different non-ionic ligands bonded to the same metal atom, although it is much easier to prepare complexes in which an anionic species is coordinated together with a neutral ligand. Secondly, although it may be possible to isolate and characterize a solid complex, quite a different complex may be the predominant species in solution. So, the blue complex Cs2[CoCl4] crystallizes 

Examples of the formation of complex ions by substitution reactions of labile complexes are the following. 

The action of excess of ammonia on aqueous solutions of copper(II) salts  

The reaction between aqueous solutions of thiourea and lead nitrate  

Numerous publications have appeared within the year which formally describe light-induced substitution of an aromatic compound. As in previous years, the current account is restricted mainly to reactions in which the light-absorbing species is the aromatic compound and the aromatic ring is directly involved. Reactions in which the substituent undergoes chemical change are only briefly mentioned, and accounts of attack of photo-generated free radicals on the aromatic species are not included. 

Reviews relevant to this section which have been published within the year describe general photo-substitution reactions,72 and the mechanism of photoaddition-substitution reactions of six-membered aza-aromatic compounds,73 but both of these are in Russian. The reactions of aromatic nitro-compounds via their triplet states have received a very comprehensive review treatment hydrogen abstraction, reduction, incorporation of solvent fragments, and addition and substitution processes have been described for a wide variety of systems.74 In view  

Castellano, J. P. Catteau, A. Lablache-Combier, B. Planckaert, and G. Allan, Khim. 

Photo-excited benzenoid compounds substituted with electron-donor groups react with both chloroform78 and carbon tetrachloride.78 79 In the former case the reaction is carried out in the presence of diethylamine, and salicylaldehyde and 

4-hydroxybenzaldehyde result from phenol via a photo-Reimer-Tiemann reaction.78 Dihydroxy-compounds, in the absence of base, yield the corresponding aldehydes and the cyclohexadienone (43). Replacement of chloroform by carbon 

During the last two decades, the volume of activation has become a recognized criterion to complement traditional investigations of the mechanisms of substitution reactions. At this stage, it may be useful to recall the classification 

For substitution reactions, the measured volume of activation, as obtained from equation (1), is usually considered to be the sum of an intrinsic contribution, resulting from changes in intemuclear distances within 

Volumes of activation for solvent exchange on high spin, first row divalent and trivalent transition metal ions are available in water and in a variety of non-aqueous solvents. The AF values indicate that the mechanism for solvent exchange is not unique, but progressively changes from an associative activation mode for the early elements to a dissociative activation mode for the later ones. 

Q Leaving solvent molecule 0 Entering solvent molecule 

Ru-O distances which are 212 pm in both complexes. For [Cp M(H20)3] (M = Rh, Ir) there is an even more dramatic increase of the water exchange rate constant (14 orders of magnitude) when compared with the corresponding hexaaqua-ion [M(H20)6p. This increase in reactivity is also related to a mechanistic changeover from an mechanism towards a more dissociative activation mode. In both cases the rhodium compound is significantly more reactive than the iridium one. 

As mentioned previously, although the benzene ring is unsaturated it is generally very stable and does not give the typical addition reactions of unsaturated compounds. Its reactions are generally substitution reactions. 

Consider the reaction between benzene and nitric acid (in the presence of concentrated sulfuric acid) with the mixture kept below 50 °C (Figiue 6.3.8). 

The concentrated sulfuric acid helps to make the ions, NO2, needed for the reaction. This positive ion is attracted to the high electron density in the benzene ring. Notice how one hydrogen was replaced by a nitro group. 

Stronger conditions bring about further nitration 

Other reagents substitute groups into different positions. It is always the first substituent on the ring that determines the position of entry of the second group. 

The six-membered-ring dianion A is found to be 22.6 kcal/mol more stable than the four-membered-ring anion B . This result is confirmed by experiments, which show that substitution reactions occur at the six-membered-ring system. 

Because of the weakness of the Si-N bond, ring cleavage of cyclosilazanes occurs upon treatment with halides of main group elements. For more than 20 years after the synthesis of the six-membered ring (Me2SiNH)3, only the substitution reaction of the N-bonded hydrogen by one trimethylsilyl group was known.30 

The six-membered (Si-N) ring crystallizes in a boat conformation.37 The nitrogen atoms exhibit a planar environment, E° N — 359.6°. The Si-N bonds have a length of approximately 174 pm. 

The lithium salt shown in Fig. 8 crystallizes from THF as a dimer in a boat conformation with a planar (Li-N)2 ring. The partially anionic Li-N bond causes increasing electron density at the nitrogen atom N(l) and therefore a shortening of the N-Si bonds in its neighborhood. 

Ring couplings occur without any difficulties as well, e.g.,3 

The transition metal-catalyzed allylation of carbon nucleophiles was a widely used method until Grieco and Pearson discovered LPDE-mediated allylic substitutions in 1992. Grieco investigated substitution reactions of cyclic allyl alcohols with silyl ketene acetals such as Si-1 by use of LPDE solution [95]. The concentration of LPDE seems to be important. For example, the use of 2.0 M LPDE resulted in formation of silyl ether 88 with 86 and 87 in the ratio 2 6.4 1. In contrast, 3.0 m LPDE afforded an excellent yield (90 %) of 86 and 87 (5.8 1), and the less hindered side of the allylic unit is alkylated regioselectively. It is of interest to note that this chemistry is also applicable to cyclopropyl carbinol 89 (Sch. 44). 

Unfortunately, attempts to perform this substitution reaction on cyclohexenol and geraniol led to the exclusive formation of the corresponding silyl ethers. It thus would seem that one requirement for effective carbon-carbon bond formation is that allylic alcohols be secondary and have possess y,y-disubstitution. Pearson, however, discovered a method with less restriction on the natiue of the substrate he used allylic acetates with y-mono-substitution or primary alcohols [96]. Not only ketene silyl acetals but also a diverse set of nucleophiles including aUyl silane, indoles, MOM vinyl ether, trimethylsilyl azide, trimethylsilyl cyanide, and propargyl silane participate in the substitution of y-aryl allylic alcohol 90 to give allylated 91 (Sch. 45). Further experimental evidence suggests that these reactions proceed via ionization to allylic carboca-tions—alcohols 90 and 92 both afforded the identical product 93. 

Grieco improved the above methods, developing a general allylation method for indoles employing y,y-disubstituted allylic alcohols. Allylic alcohol 94 underwent no reaction under conditions similar to those affording effective allylation of 95 by use of y-aryl allylic alcohol 90. By contrast, in an LPDE solution containing a catalytic amount of AcOH (1 mol %), the rapid consumption of 94 proceeded to give the indole substitution product 96 in 77 % yield. Particularly noteworthy is that the iso- 

An even more interesting result, recently obtained with LiAl[OC(Ph)(CF3)2]4 (107), is applicable to similar allylic substitutions. Reagent 107 is readily prepared by treatment of a toluene suspension of LiAlH4 with 4 equiv. HO-C(Ph)(CF3)2 under reflux conditions. The X-ray crystal structure of 107 shows that the lithium is hexa-coordinated with two internal oxygen and four internal fluorine atoms. By use of 10 mol % 107, cyclohexenyl acetate 108 and Si-3 were coupled successfully to furnish 109 in 92 % yield (Sch. 51) [100]. 

Mukaiyama and co-workers revealed that Li salts play a significant role in controlling the novel stereochemical preference that is involved in the glycosidation with ribofur-anose derivatives (Sch. 52). In particular, LiC104 [101-105] and LiNTf2 [105] were found to be effective additives in the stereocontrolled synthesis of a-o-ribofuranosides from 2,3,5-tri-O-benzyl-D-ribofuranose and several alcohols, whereas p anomers were formed in the absence of the lithium salts. Sch. 52 shows several examples that emphasize general characteristics with or without the addition of lithium salts. In the most recently advanced system (Sch. 53), a hypothetical mechanism of this reverse stereocontrol to yield 110 with the influence of lithium salt is also discussed. In the presence of 10 mol % TrC104, both pure a anomer 110 (a /3 = 99 1) and P anomer 111 a-.p = 1 99) isomerized to afford a P anomer-rich mixture (a p = 6 94). 

This chapter presents computational studies of organic reactions that involve anions. These reactions are usually not grouped together in textbooks. However, these reactions are fundamentally variations on a theme. Anions, acting as nucleophiles, can attack sp carbon atoms we call these as nucleophilic substitution reactions that follow either the S l or 8 2 mechanism. Reactions where the nucleophile attacks sp or sp carbon atoms are addition reactions. The 1,2- and 

4-addition reactions follow the classic addition mechanism, where the nucleophile adds first followed by the addition of an electrophile. Other nucleophilic reactions at carbonyl compounds, especially carboxylic acid derivatives, follow the addition-elimination pathway. 

In this chapter, we present the contributions of computational chemistry toward understanding the mechanism and chemistry for three reactions involving nucleophilic attack. The 8 2 reaction, with emphasis on the gas versus solution phase, is presented first Next we describe the critical contribution that computational chemists made in developing the theory of asymmetric induction at carbonyl and vinyl compounds. The chapter concludes with a discussion on the collaborative efforts of synthetic and computational chemists in developing organic catalysts, especially proline and proline-related molecules, for the aldol, Mannich and Michael reaction, and other related reactions. 

Nucleophilic substitution reactions are among the first synthetic transformations introduced to beginners learning organic chemistry. The mechanisms for these 

Computational Organic Chemistry, Second Edition. Steven M. Bacfarach 2014 John Wiley Sons, Inc. Published 2014 by John Wiley Sons, Inc. 

Stannyl cuprates couple with vinyl halides or triflates [16c-d, 85], and a vinyl stannane produced this way has been used in the synthesis of 7-[( )-alkylidene]-cephalosporins [117]. Vinyl substitution reactions starting from dihydrofurans are 

Furthermore, the copper-mediated SN2 substitution reaction is not restricted to carbon-carbon bond formation, as can be seen form the synthesis of silylallenes [15], stannylallenes [16] and bromoallenes [17] using propargylic electrophiles and the corresponding heterocuprates. The resulting allenes are often used as intermediates in target-oriented synthesis, e.g. in cyclization and reduction reactions [15-17]. 

The effectiveness of dimethyl sulfide as an additive for the selective formation of anti-product 22 from propargyl epoxide 20 may be due to the formation of stabilized copper species, which are less prone to undergo electron transfer processes. In this respect, other soft ligands which bind strongly to copper, in particular phosphines and phosphites [8h-j, 25, 28], have been used even more frequently. These additives also serve to suppress the formation of a common side product, i.e. an allene containing a hydrogen atom instead of the carbon substituent which should 

MeMgBr / nBu3P fiuMgCI / (EtO)3P nHexMgBr / (EtO)3P /PrMgCI / (EtO)3P PhMgBr//tBu3P  

The M4(CO)x(PR)2 (M = Fe, Ru x = 11, 12) is an interesting case for substitution in that the unsaturated jc = 11 compounds will readily add a variety of ligands to give the saturated compounds M4(CO),iL(PR)2, which then loose CO under vacuum to generate substituted unsaturated compounds.308 The substitution reaction using bifunctional donor ligands has been used to create linked cluster units.319 Substitution reactions of the related cluster system Co4(CO)10(PPh)2 have also been reported.325,326 Like several other clusters noted previously, substitution reactions of Co4(CO)10 (PPh)2 are catalyzed by electron-transfer reactions. 

The nitrido clusters [Fe4(CO)12N] and Fe4(CO)n(NO)N undergo substitution reactions yielding mono- and disubstituted products.359 The phosphines used (PPh3 and PMe2Ph) preferred to bond to the wingtip irons in the metal butterfly. 

In some cases the ensuing reactivity of the complex is changed upon substitution. For example, the Bi[Co(CO)3L]3 L = phosphine species have exhibited no tendency to form c/oso-tetrahedral molecules like the parent L = CO complex. Presumably, the steric crowding imposed by the phosphines prevents the formation of BiCo3(CO)6L3 species. 

NO is most often a three-electron donor ligand. It can be used as the neutral molecule and in simple coordination chemistry can substitute for CO readily. Usually two NO ligands will displace three CO ligands as in the Fe(CO)5 and Fe(CO)2(NO)2 pair. A common method of producing NO-substituted compounds, however, is not the direct reaction of NO with metal fragments, but rather the use of NO+ salts (BF4 or PF6 are commonly employed) as in Eq. (242).357 For metal carbonylate anions this provides a convenient methodology. Notice that CO is still displaced in these reactions. 

Protonation reactions may be simply H+ addition in which the E-M framework of a cluster complex remains essentially unaltered. Where simple protonation is observed, conventional acid-base chemistry is involved and the site of protonation is almost always the electron-rich metal center, though protonation can sometimes be observed at E. Likewise, addition of bases to metal cluster hydrides results in the deprotonation [e.q., Eq. (243)179] Sometimes even halide ions in nonaqueous media are strong enough to deprotonate the metal centers [Eqs. (244)-(246)95 203,373]. Os- 

In the last chapter we saw the importance of nnderstanding mechanisms. We said that mechanisms are the keys to understanding everything else. In this chapter, we wiU see a very special case of this. Students often have difficulty with substitution reactions—specifically, being able to predict whether a reaction is an Sn2 or an SnI. These are different types of substitution reactions and their mechanisms are very different from each other. By focusing on the differences in their mechaiusms, we can understand why we get Sn2 in some cases and SnI in other cases. 

Four factors are used to determine which reaction takes place. These four factors make perfect sense when we understand the mechanisms. So, it makes sense to start off with the mechanisms. 

Ninety-five percent of the reactions that we see in organic chemistry occur between a nucleophile and an electrophile. A nucleophile is a compound that either is negatively charged or has a region of high electron density (like a lone pair or a double bond). An electrophile is a compound that either is positively charged or has a region of low electron density. When a nucleophile encounters an electrophile, a reaction can occur. 

In both Sn2 and SnI reactions, a nucleophile is attacking an electrophile, giving a substitution reaction. That explains the Sn part of the name. But what do the 1 and 2 stand for To see this, we need to look at the mechanisms. Let s start with Sn2  

Now we get to the meaning of 2 in Sn2. Remember from the last chapter that nucleophilicity is a measure of kinetics (how fast something happens). Since this is a nucleophilic substitution reaction, then we care about how fast the reaction is happening. In other words, what is the rate of the reaction This mechanism has only one step, and in that step, two things need to find each other the nucleophile and the electrophile. So it makes sense that the rate of the reaction will be dependent on how much electrophile is around and how much nucleophile is around. In other words, the rate of the reaction is dependent on the concentrations of two entities. The reaction is said to be second order, and we signify this by placing a 2 in the name of the reaction. 

In this reaction, there are two steps. The first step has the LG leaving all by itself, without any help from an attacking nucleophile. This leaves behind a carbocation, which then gets attacked by the nucleophile in step 2. This is the major difference between Sn2 and SnI reactions. In Sn2 reactions, everything happens in one step. In SnI reactions, it happens in two steps, and we are forming a carbocation in the process. The existence of the carbocation as an intermediate in only the SnI mechanism is the key. By understanding this, we can understand everything else. 

This also allows us to understand why we have the l in SnI. There are two steps in this reaction. The first step is very slow (the LG just leaves on its own to form C+ and LG-, which is pretty strange when you think about it), and the second 

In the presence of methanol as solvent and 1,4-dicyanobenzene as acceptor, photoinduced electron transfer from 1,4-bis(methylene)cyclohexane gives 4-(methoxymethyl)-1 -methylenecyclohexane and 4-(4-cyanophenyl)-4-(methoxy-methyl)-l-methylenecyclohexane which arise by nucleophilic attack of the solvent on the radical cations, followed either by reduction and protonation, or by combination with the radical anion of the electron acceptor.These observations are in accordance with the proposed mechanism of the nucleophile-olefin combination, aromatic substitution (photo-NOCAS) reaction. The same group has also investigated the use of cyanide ion as nucleophile and report that irradiation of a mixture of 1,4-dicyanobenzene in the presence of biphenyl as donor, KCN, and 18-crown-6 gives a mixture of (79) and (80). These workers have also extended the scope of NOCAS to fluoride ion. In particular, use of 2,3-dimethylbut-2-ene and 2-methylbut-2-ene gives 4-cyanophenyl substituted 

Irradiation of chlorobenzene solutions of [Pd(PPh3)4] produces trans-[PdCl2(PPh3)2] and a mixture of chlorobiphenyls, and irradiation of 2-amino-5-iodo-3-(N-methyl-N-tosylamino)pyridine in benzene solution gives 2-amino-3-methylamino-5-phenylpyridine by simultaneous phenylation and tosyl removal. This reaction is a key step in the synthesis of the food-borne carcinogen 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine. Substituted 1,2 -biazulenes have been prepared by photolysis of 2-diazo-l,3-dicyanoazulen-6(2H)-one in the presence of azulene derivatives.  

The use of lower temperatures in the bromate-induced monobromopenta-hydroxylation of benzene by catalytic photoinduced charge transfer osmylation favours formation of the neo diastereoisomer of the deoxybromoinositol. Photolysis of N-(diphenylamino)-2,4,6-trimethylpyridinium tetrafluoroborate and N-[bis(4-methylphenyl)amino]-2,4,6-trimethylpyridinium salts induces nucleophilic addition of various 7i-nucleophiles such as electron rich alkenes to the o- and p-positions of one of the phenyl rings.These observations are thought to imply the presence of the diarylnitrenium ion (Ar2N ) as intermediate, but evidence is also presented for the involvement of radical species, as well as for the formation of indoles and indolinones. Some MO calculations are also reported. 

The field of chemotherapy began in the mid-1930s, when scientists realized that a chemical warfare agent (sulfur mustard) could be modified and used to attack tumors. The action of sulfur mustard (and its derivatives) was thoroughly investigated and was found to involve a series of reactions called substitution reactions. Throughout this chapter, we will explore many important features of substitution reactions. 

At the end of the chapter, we will revisit the topic of chemotherapy by exploring the rational design of the first chemotherapeutic agents. 

9 Selecting Reagents to Accomplish Functional Group Transformation 

If necessary, review the suggested sections to prepare for this chapter. 

PLUS Visit www.wileyplus.com to check your understanding and for valuable practice. 

W j J Hete OotO -ncfAp Otei onrf a-Hete DatomolkyhiAp Otes O O VC iy thesls R OAc 

Sdieire 3.2fl. Steieochemlcel ecpectc of ellyllc cubctitutic end eppllcetlon In the cynthecic of (i-)-dlhydionepetelecti (m-CPBA = m-chloiopeibenzolc ecld) [106]. 

Sdi ir 3.30. Stannylciiprate ailylic ciibctltiitlon In the cyritheclc of (+)-l Ci-epl-elemol (dba = dlberizyllderieacetorie) 

Sdi ir 3.31. Synthecic or -amlno alcoholc by ao/latlon of cllylciiprater (Boc = t-biitOKycarbonyl) [11 d, 115a]. 

Sdieire 3.32. Synthecic of cllylalaninec by meanc of allcyl halide allcylation of cllylciipratec [116a]. 

An interesting property of isobenzofuran 2 is its unexpectedly high acidity. Although the pKa value has not been determined, NMR observation of the equilibrium between 2-lithiated furan and isobenzofuran established 

For the preparation of the triazine membranes, the entire solid support (cellulose or polypropylene membrane) was treated with a 5 M solution of the corresponding amine in NMP and a 1 M solution of cesium phenolate in DMSO (2 pi each at one spot) and subsequently heated using microwave irradiation (domestic oven) for 3 min. After washing the support successively with DMF, methanol and DCM (three times each), the membrane was air dried. 

A similar approach has been described by the same authors for the synthesis of related cyclic peptidomimetics37. A set of ten nucleophiles were employed for the substitution 

In conclusion, it has been shown that microwave heating is a powerful tool for nucleophilic substitutions on solid support, as conversion rates are significantly enhanced and reaction times can be drastically reduced compared to conventional heating. 

When a large amount of heat and light is used, radicals of Cl and CH are formed and the reaction occurs in a series of steps, hv 

The C — H bonds in alkanes are broken to form nitroalkanes with nitric acid at 400°C or more. 

If propane is nitrated, a mixture of 1-nitropropane and 2-nitropropane, nitromethane and nitroethane is produced. 

The composition of natural gas varies in different localities. Its main component, methane, usually makes up 80% to 95% and the rest is composed of varying amounts of ethane, propane and butane. 

A mixture of propane and butane (LPG liquefied petroleum gas) is used as fuel for cooking. 

A mechanism for carbon-carbon bond formation involving 8 2 displacement at carbon is consistent with the above observations. Two possible pathways for coupling were mentioned 297) (1) a simple displacement of halide by an alkyl group [Eq. (60)], and (2) displacement of the halide by the copper atom s d electrons, with inversion of configuration, to form a copper(III) species which decomposes with retention of 

The consensus favors a transitory copper(III) intermediate in the reaction of a copper corapound with an alkyl or vinyl halide 37, 57, 65, 185, 297), although Tamura and Kochi consider such an intermediate unlikely for alkyl halides (276). Collman (57) has suggested that organocopper compounds are representative of a number of transition 

A slightly different mechanism has been proposed by Cairncross and Sheppard (37) for the reaction of fluoroarylcopper compounds with substituted alkyl halides. Pentafluorophenylcopper can form a complex with bicyclooctyl bromide by coordination with the halogen atom. Such a complex may go directly to coupled product in a four-center process, or, depending on the nature of the group attached and the nature of the alkyl moiety, may form an ion pair which collapses to the coupled 

Burdon et al. 31) have proposed that aryl and vinyl halides, but not alkyl halides, couple with copper compounds via a four-center transition state (XI). Nucleophilic substitution of vinylic bromides by organo- 

There is presumably more than a subtle difference between the reactions of alkyl and aryl halides with organocopper compounds, as a straightforward nucleophilic displacement of aryl halide by the d electrons of a copper species is hardly likely. Simple aryl halides are nearly all inert to the usual nucleophiles, such as alkoxides, unless strongly activated by electron-attracting groups in the ortho and para positions. However, coordination of the halogen to copper may be sufficient to 

An Sj l mechanism has been implicated in the photochemical reaction of diarylsulphides (and the corresponding sulphoxides and sulphones) with the enolate of pinacolone, and with diphenylphosphide anion and diethylphosphite anion.The products are derived from reaction of the anions with aryl radicals formed by cleavage of an aryl sulphur bond in a diarylsulphide radical anion intermediate. Thus (146) is formed from diphenylsulphide and the enolate of pinacolone. 

The effect of variation of solvent and concentration of reactants in the Sjy l reaction between benzene selenate (PHSe ) and aryl halides has been studied. Evidence was found to suggest that the radical anion derived from combination of the benzene selenate anion and aryl radicals (see scheme 4) is formed reversibly and can also dissociate to generate phenyl radical and aryl selenate anion. 

Thus photolysis of phenyl selenate with 4-iodoanisole yielded diphenyl selenide and his-(4-methoxyphenyl) selenide, in addition to the expected product, phenyl 4-methoxyphenyl selenide. 

It was reported several years ago that ultra-violet light irradiation of the anion of indole with 2-fluoropyridine yields N-(3-pyridyl)indole. The authors have now examined the same reaction for 

3- and 4-fluoropyridine. With 3-fluoropyridine some N-(3-pyridyl)-indole was obtained however, the photochemical coupling fails for 4-fluoropyridine. 

The efficiency of phenol formation from the irradiation of benzene in aqueous solution is reported to be pH dependent with, not surprisingly, an increase in yield with increase in pH. A mechanism is proposed in which the hydroxylation occurs by attack of either water or a hydroxyl species on benzene. In other studies, phenol formation was studied using six different types of hydroxy-radical source and over a wide range of reactant concentrations. Conditions were evolved which gave quantum yields of phenol production of approximately twice those previously recorded and it is deduced that most, if not all of the phenol arises directly from the reaction of oxygen with the benzene-OH adduct. 

It is reported that 1,4-dibromonaphthalene can be formed selectively and in 90% yield by irradiation of naphthalene and 1-bromonaphthalene with stoichiometric amounts of bromine and with the minimum amount of CH2CI2 as solvent at —30 to — SO C. In contrast, l,2,3,4,5-pentabromo-l,2,3,4-tetrahyd-ronaphthalenes result from irradiation of 1-bromonaphthalene in CCI4 at — 30°C, whereas at 77°C only 1,5-dibromonaphthalene is formed and in 80% yield. Two of the more unusual examples of the photoinduced introduction of groups into aromatic rings which have been described within the year are the formation of 1-cyanopyrene in a yield of up to 73% from irradiation at the interface of a solution of pyrene and 1,4-dicyanobenzene in propylene carbonate and an aqueous solution of NaCN in a polymer microchannel chip, and the addition of a variety of groups e.g. NH2, OMe, CN, and CO2H) to coronene by irradiation of arene-ice mixtures at low temperature and pressure. The latter work provides the first experimental evidence that such functionalized arenes, which are detected in primitive meteorites and interplanetary dust particles, may have arisen, at least in part, from photochemistry in ice. 

4-Dimethylbenzodiazepine was mono-JV-tosylated by means of tolu-ene-p-sulfonyl chloride in pyridine.40 

In basic conditions both the 3-methylene group and 2(4)-methyl groups should be susceptible to electrophilic attack owing to the adjacent imine groups. 2,4-Dimethylbenzodiazepine reacted with methyl iodide in liquid ammonia to give 2,3,4-trimethylbenzodiazepine.5 

With aryl aldehydes in the presence of base, 2,4-dimethylbenzo-diazepine undergoes condensation at the methyl groups to give mono or bis benzylidene derivatives 5 44 2,4-diphenylbenzodiazepine would not condense with benzaldehyde.9 

4-Dimethyl- and 2-methyl-4-phenylbenzodiazepines reacted with oxalic ester at both the 3-position and 2-methyl group to give products 

6 44 51 In the case of 2-methyl-4-phenyldiazepine, the 2-oxalyl derivative could also be obtained under different conditions.44 Halogen atoms substituted on 2(4)-methyl groups readily undergo nucleophilic substitution thus 2,4-bis(bromomethyl)benzodiazepine gives the 2,4-bis(iodomethyl) analog with sodium iodide in acetone.11 

2-thiobenzothiazolyl) on alkylation, this gives (109 R = alkyl, R as before), 

Zelenska, V. Madajova, and I. Zelensky, Chem. Zvesti, 1978, 32, 658 (Chem. Abstr., 1979, 91, 

Sugimura, and H. Okamura, Chem. Lett., 1979, 1447. 

Acetoxymethylation (Prins reaction) of longifolene proceeds smoothly to yield co-acetoxymethyl longifolene which was shown to possess the -configuration (59) (48). The product was converted into a number of related compounds (60—64). 

R = CH20Ac R = CH20H R = CH20Me R = CHO R=COOH R=COOMe R = COMe 

Acylation of longifolene with BF3 Et20 and acetic anhydride gives 30—40% of co-acetyllongifolene (65), the stereochemistry of which rests on its hypochlorite oxidation to the known (63) 31). Isolongifolene (23) is the major by-product of the reaction. 

Exposure of longifolene to manganic acetate in refluxing acetic acid-acetic anhydride furnished in poor yield (9%) the product (66), the stereochemistry of which remains unresolved. Under the same conditions, camphene gave in 30% yield y-lactone mixture (67), in which one isomer predominated 49). A carboxymethyl radical arising from the thermolysis of Mn (III) acetate is considered to be the reactive species in such reactions (50). 

CH3(CH2).,CH20H + SOCIj— CH3(CH2)4CH2CI + SOj + HCl Relative molecular masses 

Fill in the blanks below. To verify that your answers are correct, look in your textbook at the end of Chapter 7. Each of the sentences below appears verbatim in the section entitled Review of Concepts and Vocabulary. 

Evidence for the concerted mechanism, called Sn2, includes the observation of a  

SkillBuilder 7.1 Drawing the Curved Arrows of a Substitution Reaction 

A quinine alkaloid derivative containing a vinyl group, such as 252, has been hydroborated, undergo a boron-zinc exchange and copper(I)-catalyzed allylation, leading to the alkaloid derivative 253 103b]. A new route to hydrophobic amino- 

Interestingly, this substitution reaction can be applied to the stereoselective assembly of chiral quaternary centers. The trisubstituted allylic pentafluorobenzoates ( )- and (Z)-276 readily undergo a substitution reaction at -10 °C with Pent2Zn furnishing the enantiomeric products (S)- and (R)-277 with 94% ee. 

Alkynyl iodides and bromides smoothly react with various zinc-copper organometallics at -60 C leading to polyfunctional alkynes [48dj. lodoalkynes, such as 296 [188] react at very low temperature, but lead in some cases to copper acetylides as byproducts (I/Cu-exchange reaction). 1-Bromoalkynes are the preferred substrates. Corey and Helel have prepared a key intermediate 297 of the side chain of 

---

Azulene is an aromatic compound and undergoes substitution reactions in the 1-position. At 270 C it is transformed into naphthalene. 

It is a typically aromatic compound and gives addition and substitution reactions more readily than benzene. Can be reduced to a series of compounds containing 2-10 additional hydrogen atoms (e.g. tetralin, decalin), which are liquids of value as solvents. Exhaustive chlorination gives rise to wax-like compounds. It gives rise to two series of monosubstitution products depending upon... 

Octahedral substitution reactions (e.g. those involving cobalt(III) complexes) may proceed by both Sf l or 8 2 reactions. In the S l case a slow dissociative mechanism (bond breaking) may take place. Reaction with the substituting... 

Prisner T F, van der Est A, BittI R, Lubitz W, Stehlik D and Mdbius K 1995 Time-resolved W-band (95 GHz) EPR spectroscopy of Zn-substituted reaction centers of Rhodobacter sphaeroides R-26 Chem. Phys. 194 361-70... 

Discuss (a) the acidity and (b) the substitution reactions of metal hexa-aquo cations. [MfH O) ]" (where n = 2 or 3), giving two examples of each type of reaction. Discuss the effect upon the stabilities of the -t- 2 and -f- 3 oxidation states of... 

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. 

A brief account of aromatic substitution may be usefully given here as it will assist the student in predicting the orientation of disubstituted benzene derivatives produced in the different substitution reactions. For the nitration of nitrobenzene the substance must be heated with a mixture of fuming nitric acid and concentrated sulphuric acid the product is largely ni-dinitrobenzene (about 90 per cent.), accompanied by a little o-dinitrobenzene (about 5 per cent.) which is eliminated in the recrystallisation process. On the other hand phenol can be easily nitrated with dilute nitric acid to yield a mixture of ortho and para nitrophenols. It may be said, therefore, that orientation is meta with the... 

The proton of terminal acetylenes is acidic (pKa= 25), thus they can be deprotonated to give acetylide anions which can undergo substitution reactions with alkyl halides, carbonyls, epoxides, etc. to give other acetylenes. 

The results in table 2.6 show that the rates of reaction of compounds such as phenol and i-napthol are equal to the encounter rate. This observation is noteworthy because it shows that despite their potentially very high reactivity these compounds do not draw into reaction other electrophiles, and the nitronium ion remains solely effective. These particular instances illustrate an important general principle if by increasing the reactivity of the aromatic reactant in a substitution reaction, a plateau in rate constant for the reaction is achieved which can be identified as the rate constant for encounter of the reacting species, and if further structural modifications of the aromatic in the direction of further increasing its potential reactivity ultimately raise the rate constant above this plateau, then the incursion of a new electrophile must be admitted. 

The above definition implies that the reactivity of an aromatic compound depends upon the reaction which is used to measure it, for the rate of reaction of an aromatic compound relative to that for benzene varies from reaction to reaction (table 7.1). However, whilst a compoimd s reactivity can be given no unique value, different substitution reactions do generally set aromatic compoimds in the same sequence of relative reactivities. 

The selectivity relationship merely expresses the proportionality between intermolecular and intramolecular selectivities in electrophilic substitution, and it is not surprising that these quantities should be related. There are examples of related reactions in which connections between selectivity and reactivity have been demonstrated. For example, the ratio of the rates of reaction with the azide anion and water of the triphenylmethyl, diphenylmethyl and tert-butyl carbonium ions were 2-8x10 , 2-4x10 and 3-9 respectively the selectivities of the ions decrease as the reactivities increase. The existence, under very restricted and closely related conditions, of a relationship between reactivity and selectivity in the reactions mentioned above, does not permit the assumption that a similar relationship holds over the wide range of different electrophilic aromatic substitutions. In these substitution reactions a difficulty arises in defining the concept of reactivity it is not sufficient to assume that the reactivity of an electrophile is related... 

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). 

In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, selenophene[233,234], and cyclobutadiene iron carbonyl complexpSS] react with alkenes to give vinyl heterocydes. The ease of the reaction of styrene with sub.stituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

The ij-arylpalladium bonds in these complexes are reactive and undergo insertion and substitution reactions, and the reactions offer useful methods for the regiospecific functionalization of the aromatic rings, although the reac-... 

The diazonium salts 145 are another source of arylpalladium com-plexes[114]. They are the most reactive source of arylpalladium species and the reaction can be carried out at room temperature. In addition, they can be used for alkene insertion in the absence of a phosphine ligand using Pd2(dba)3 as a catalyst. This reaction consists of the indirect substitution reaction of an aromatic nitro group with an alkene. The use of diazonium salts is more convenient and synthetically useful than the use of aryl halides, because many aryl halides are prepared from diazonium salts. Diazotization of the aniline derivative 146 in aqueous solution and subsequent insertion of acrylate catalyzed by Pd(OAc)2 by the addition of MeOH are carried out as a one-pot reaction, affording the cinnamate 147 in good yield[115]. The A-nitroso-jV-arylacetamide 148 is prepared from acetanilides and used as another precursor of arylpalladium intermediate. It is more reactive than aryl iodides and bromides and reacts with alkenes at 40 °C without addition of a phosphine ligandfl 16]. 

Terminal alkynes undergo the above-mentioned substitution reaction with aryl and alkenyl groups to form arylalkynes and enynes in the presence of Cul as described in Section 1.1.2.1. In addition, the insertion of terminal alkynes also takes place in the absence of Cul, and the alkenylpalladium complex 362 is formed as an intermediate, which cannot terminate by itself and must undergo further reactions such as alkene insertion or anion capture. These reactions of terminal alkynes are also treated in this section. 

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. 

III. Reactivity of the Selenazole Ring 1. Electrophilic Substitution Reactions... 

The most widely studied electrophilic substitution reactions are haloge-nation and nitration. Two main types of substrates are possible alkyl-thiazoles and arylthiazoles. 

The intervention of ion pairs, more important in t-butanol than in methanol, can increase the substitution reaction in such cases as the 4-and 5-halogenothiazoles, which are poorly activated by the aza substituent. 

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... 

All the halogenothiazoles, depending on the electron-withdrawing power of the halosubstituent, together with the electron-withdrawing power of the azasubstituent, are only slightly susceptible to electrophilic substitution reactions such as nitration, sulfonation, and so on, while the polyhalogenatjon reaction can take place. 

The 2-nitrothiazole can be reduced to the corresponding aminothiazole by catalytic or chemical reduction (82, 85, 89). The 5-nitrothiazole can also be reduced with low yield to impure 5-aminothiazole (1, 85). All electrophilic substitution reactions are largely inhibited by the presence of the nitro substituent. Nevertheless, the nitration of 2-nitrothiazoIe to 2,4-dinitrothiazole can be accomplished (see Section IV). 

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). 

The very high rate of thiophenoxy substitution, compared with low stability of Meisenheimer-like sulfurated compounds, can explain the simple behavior of the ihiophenoxy-substitution reaction. 

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