Intramolecular nucleophilic reactions

As we have seen (Section 4, p. 191) the range of effective molarities associated with ring-closure reactions is very much greater than that characteristic of intramolecular general acid-base catalysis the main classification is therefore in terms of mechanism. By far the largest section (I, Tables A-D) gives EM s for intramolecular nucleophilic reactions. These can be concerted displacements (mostly at tetrahedral carbon), stepwise displacements (mostly addition-elimination reactions at trigonal carbon), or additions, and they have been classified in terms of the nucleophilic and electrophilic centres. 

Fig. 5.8. An a-amino group in the acylamido side chain off)-lactams increases the rate of degradation in alkaline media by favoring an intramolecular nucleophilic reaction yielding piper-azine-2,5-dione products (e.g., 5.31 and 5.33). a) a-(2-Amino-2-phenylacetyl)cephalosporins b) arylglycine-substituted monobactams c) 6a-epiampicitlin (5.32). 

Intramolecular nucleophilic reactions could also be facilitated over their intermolecular counterparts if the reaction centre and the nucleophile are compressed in the ground state. Part of the van der Waals repulsion energy could thereby be overcome in the ground state, resulting in a more favourable A// value. Solvation... 

Intramolecular nucleophilic reaction of sp2-geminated organodimetal species gives cycloalkyl metal derivative, which can be converted into the corresponding alkenyl iodide. The iodide can be used for further transition-metal-catalyzed cross-coupling reaction (equations 61 and 62)86. 

A special case of an intramolecular nucleophilic reaction on the sterically hindered anion of 5-acetoxy-8-tert-butyl-2-hydroxy-l-(2-pyridyl)naphtha-lene (27) was performed by anodic oxidation.74 The product is the isolable perchlorate 28, which slowly loses isobutylene to give the zwitterion 29 [Eq. (33)]. 

Indole, 2-acyl-1-benzenesulfonyl-intramolecular nucleophilic reactions, 4, 244 Indole, 1-acyloxy-synthesis, 4, 364 Indole, alkoxy-synthesis, 4, 367 Indole, 1-alkoxy-synthesis, 4, 364 Indole, 4-alkoxy-synthesis, 4, 328 Indole, 2-alkoxycarbonyl synthesis, 4, 337 Indole, alkyl-... 

Rearrangement of the mesoionic imines (141) to (142 Scheme 49) is an intramolecular nucleophilic reaction (74JCS(P1)627). Both (141) and (142) are accessible through unambiguous syntheses. 

Another possible mechanism for the final stages of the reaction involves an intramolecular nucleophilic reaction ... 

The HCl that is produced can add in a regiospecific manner to the isolated double bond, giving a tertiary carbocation. An intramolecular nucleophilic reaction with this cation generates the product. 

Because C-3 becomes attached to C-2, a nucleophilic reaction of the nitranion at the electrophilic carbonyl carbon must take place. Sterically this carbon is the most accessible. This step is followed by an intramolecular nucleophilic reaction of the alcoholate with the adjacent carbon (numbered 1 in the previous equation). 

In these reactions the nucleophilic carbanion is produced either by deprotonation or by metal reduction of a C-halogen bond. It is interesting to note that, as in other cyclopropane formation reactions , even a sluggish nucleofuge such as EtO" can be displaced in these intramolecular nucleophilic reactions (equation 5). 

Below, the usefulness of nucleophile- and base-labile linkers and resins is reviewed in the preparation of various organic compounds. First, intermolecular nucleophilic displacement (saponification, transesterification and amminolysis and related reactions) are analyzed. Finally, the obtention of cyclic products by intramolecular nucleophilic reactions is reviewed. 

Substitution of CO by phosphines 145 The Dotz reaction 149 Rearrangement reactions with loss of CO 151 Photochemical reactions 153 Reactions at the carbene carbon 158 General features 158 Amine nucleophiles 159 Phospine and phosphite nucleophiles 167 Alcohols and alkoxide ion nucleophiles 171 Thiol and thiolate ion nucleophiles 179 Intramolecular nucleophilic reactions 191 Hydroxide ion and water as nucleophiles 194 Insertion reactions initiated by nucleophilic attack Acid-base reactions at the a-carbon 207 General features and methods 207 Kinetic and thermodynamic acidities 209 Effect of structure on pKa values 210 Intrinsic rate constants for proton transfer 219 Thermodynamic acidities in organic solvents 223 Hydrolysis of ionizable carbene complexes 228 Acknowledgments 232 References 233... 

There is little effect of micelles upon the rate of an intramolecular nucleophilic reaction. Micelles of hexadecyltrimethylammonium bromide catalyse, by factors of 10 —10, the arenesulphinate anion-induced hydrolysis of 4-tolylsulphonyl-methyl perchlorate. There is no relationship between the rate acceleration and hydro-phobicity of the sulphinate anion and catalysis is attributed to the concentration of the reactants in the micellar phase.The rate constants for the reaction of nucleophiles with carbonium ions and those for the addition of cyanide ion to the A -alkylpyridinium ions are similar in the micellar and aqueous phases, and the rate enhancement is due to the concentration of reactants in the micellar pseudophase. Similarly, although micellar catalysed dephosphorylation by nucleophiles may show rate enhancements of up to 4 x 10 -fold, the second-order rate constants may be slightly smaller in the micellar pseudophase lowing to its lower polarity. However, the reaction of fluoride ion with 4-nitrophenyldiphenyl phosphate is very rapid in micelles of cetyltrimethylammonium fluoride, but the rate constant continues to increase when the substrate is fully bound with increasing cetyltrimethylammonium fluoride or sodium fluoride. The failure of the micellar pseudophase model is also apparent in the reaction of hydroxide ion with 2,4-dinitrochlorobenzene. It is suggested that reaction occurs between reactants in the aqueous and micellar pseudophases and also between hydroxide ion in water and substrate in the micelle. ... 

After nucleophilic attack on the central allenyl carbon, the resulting n-allyl intermediate is trapped by an intramolecular nucleophilic reaction, giving the initial 3-alkylidene-2,3-dihydrofuran product, and regenerating the palla-dium(O) catalyst. A mildly acidic work-up allows aromatisation, giving the final product. 

A plausible mechanism of the reaction involves the formation of compound 406 by the nucleophilic substitution by 405 on 2-halonitroarenes 383, 404 or 1,2-dihalobenzenes (see Sect. 2.7.3) and the formation of carboxamide anion 408. Finally, an intramolecular nucleophilic reaction of 408 with the displacement of the leaving group by carboxamide anion would lead to pyrrolo[l,2-a]quinoxaline 406 (Scheme 2.73). 

The CpCo(CO)2 (10 mol %) catalyzed reaction of diyne 125 and cyanomesylate 126 under microwave heating (120 °C) delivered dehydrotylophorine (127) directly in 78% yield. Notably, during the course of this reaction cascade, the nonnucleophilic N-center of a nitrile is converted into a nucleophilic pyridine moiety that subsequently undergoes an intramolecular nucleophilic reaction with the tethered sulfonate leaving group. This facile tandem reaction has also been used in a synthetic approach to the spiroindolinone framework of the marine alkaloids citranin A and B [38]. 

Induced Intramolecular Nucleophilic Reaction Such a reaction involves the formahon of an addition covalent adduct between electrophihc and nucleophilic reactants in the inihal step followed by intramolecular reachon in the subsequent step of the reachon. An example of such a reachon is the methanolysis of 4-methoxyphenyl 2-foimylbenzenesulfonate in basic media. The reaction of methanol with 4-methoxyphenyl 2-formylbenze-nesulfonate (11) in the presence of anhydrous potassium carbonate gives the dimethyl acetal of 2-formylbenzenesulfonic acid in exceUent yield. But the reac-... 

Reports on the rate enhancements in intramolecular nucleophilic reactions compared to analogous intermolecular nucleophilic reactions are plenty. But such reports on induced intramolecular or intramolecular induced nucleophilic catalysis are rare. One might argue that the induced intramolecular/intramolecular induced nucleophilic reactions also represent the corresponding nucleophilic catalysis. But this statement is not totally correct in view of the definition of a catalyst. For example, hydroxide-ion-catalyzed second-order rate constant (koe) for the cleavage of one of the two amide bonds in N,N-dimethylphthalamide (13) at 25.3°C is 7.6 sec. The value of koe for the cleavage of amide bond in... 

Occasionally, the presence of boric acid in the reaction mixture increases the rate of reaction because of the change in the nature of reaction from intermolecular reaction to intramolecular reaction owing to complex formation between the reactant and boric acid. Such rate enhancement is sometimes described as induced catalysis. This terminology is correct only if boric acid has lower (compared to the reactant) or no binding or reaction affinity with the products. When products react or complex with boric acid with the same or greater affinity as with the reactants, then such a rate enhancement is more correctly described as boric-acid-induced intramolecular nucleophilic reaction. 

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