Intramolecular induced nucleophilic reaction

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-... 

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. 

A variety of silicon-functionalized diazoacetic esters are available by reacting (trifloxysilyl)- or (chlorosilyl)diazoacetic esters with appropriate nucleophiles [1]. Thermally, photochemically, or transition metal induced intramolecular carbene reactions of these novel diazoesters lead to four-, five-, and six-membered silaheterocycles. 

Thionyl chloride undergoes a cyclization reaction with ketones. Enoli-zation of the intermediate sulfenyl chloride, followed by the base-induced intramolecular nucleophilic displacement reaction, produces the thietanone... 

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. ... 

Induced intramolecular nucleophilic catalysis involves the formation of a molecular addition complex (Ad) between the reactant/substrate (R-A) and catalyst (W-B) followed by intramolecular nucleophilic substitution reaction between two reaction sites A and B giving products P3 and P4, where one of the products, say P4, is unstable, i.e., more reactive, and, hence, P4 undergoes further reaction to reproduce catalyst (W-B) and give the final stable product P5. This whole chemical process may be shown by Equation 2.27. Intramolecular induced nucleophilic catalysis involves the intermolecular nucleophihc substitution reaction between R-A and catalyst, (C-W-B), where nucleophilicity of the nucleophile is enhanced owing to intramolecular interaction between molecular sites B and C of catalyst. 

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... 

Induced Intramolecular Nucleophilic Catalysis Nature s most efficient catalysts often bring about the maximum possible reduction in the overall free energy of activation for both simple and extremely complex reactions. The molecular machinery involved in reactions of these catalysts is fascinating and awesome, and gives rise to the idea of designing synthetic catalysts that could mimic some, if not all, the characteristic molecular features of Nature s catalysts. Perhaps, this is the fastest way to come up with an efficient catalyst for a specific purpose. In order to synthesize such a cost-effective catalyst, it is essential to know the fine details of the mechanism of the reaction catalyzed by Nature s catalyst. This aspect of such effort is indeed extremely difficult, if... 

The intramolecular Michael addition11 of a nucleophilic oxygen to an a,/ -unsaturated ester constitutes an attractive alternative strategy for the synthesis of the pyran nucleus, a strategy that could conceivably be applied to the brevetoxin problem (see Scheme 2). For example, treatment of hydroxy a,/ -unsaturated ester 9 with sodium hydride furnishes an alkoxide ion that induces ring formation by attacking the electrophilic //-carbon of the unsaturated ester moiety. This base-induced intramolecular Michael addition reaction is a reversible process, and it ultimately affords the thermodynamically most stable product 10 (92% yield). 

Lithium tributylmagnesate induced iodine-magnesium exchange reaction of 5-alkoxy-3-iodomethyl-l-oxacyclopentanes (Scheme 16). A following intramolecular nucleophilic substitution led to construction of a cyclopropane with concomitant opening of the oxa-cyclopentane ring. 

Hexane-1,6-diol was found to undergo an oxidation-cyclization process at elevated temperatures (250 °C) in the presence of a Cu-Cr catalyst supported on kieselguhr to yield 2,3,4,5-tetrahydrooxepin (68) (65JOC335). The final stage of the latter reaction involves a dehydration of the hemiacetal 2-hydroxyoxepane (75) as indicated in equation (38). An alternative type of base-induced cyclization (equation 39) involving intramolecular nucleophilic attack has been used in the synthesis of 4-ethoxycarbonyI-2,3,6,7-tetra-hydrooxepin (153) (73JOC1767). 

There has been a study of photo-induced intramolecular cyclization of some o-haloarylheterylamines which may lead to pyridof 1,2-a]benzimidazole derivatives.51 Several studies have been reported of photochemical nucleophile-olefin combination, aromatic substitution (photo-NOCAS) reactions with fluoride,52 cyanide,53 or acetonitrile54 acting as the nucleophile, hi the example illustrated in Scheme 3,... 

Ring-constrained analogues 37 of the anti-inflammatory drug, diclofenac, have been prepared by acid-catalyzed condensation of aldehydes (or ethylene ketals of ketones) with 36 (Equation 4) <1998MI201>. This reaction presumably proceeds via intramolecular nucleophilic attack by the carboxylic acid group on an iminium ion intermediate from condensation of the secondary amine. Interestingly, the compounds 37 showed comparable activities to diclofenac in the formalin-induced rat paw edema test. 

Intramolecular nucleophilic substitution reactions of phenol ether derivatives induced by activated iodine(III) reagents such as PIFA-TMSOTf and PIFA-BF3 Et20 [Eq. (7) - (11)] have been applied to total or formal synthesis of various types of bioactive natural products. 

Nakadaira, Y., Sekiguchi, A., Funada, Y., and Sakurai, H. (1991) Photo-induced electron transfer reaction of polysilanes, intramolecular trapping of a transient radical cation with a nucleophile. Chemistry Letters, 327-330. 

The study of gas-phase acid-induced nucleophilic displacement on 2,3-dihalobutanes has provided stereochemical evidence for the occurrence of cyclic chloronium and bromo-nium ions (X = Cl, Br), but not fluoronium ions17. Protonation or methylation of the neutral 2,3-dihalobutane by a suitable acid GA+ produces a halonium intermediate 2, which in the presence of water ultimately leads to the corresponding halohydrin neutral product (Scheme 4). Analysis of these neutral products indicated that the reaction proceeds with retention of configuration when X = Cl, Br and with inversion of configuration when X = F. The results were rationalized by the mechanisms sketched in Scheme 4, namely direct bimolecular nucleophilic displacement by H20 on 2 when X= F and intramolecular nucleophilic displacement to convert 2 into the cyclic halonium ion 3 (with inversion of configuation) followed by bimolecular nucleophilic displacement on 3 (with inversion of configuration) when X = Cl and Br. 

Although, in general, the -excessive nature of the heterocyclic rings under discussion reduces their reactivity to nucleophilic substitution, there are a number of reactions in which the leaving group is a nitro group. An example of intramolecular nucleophilic displacement of a pyrrole nitro group is provided by the base-induced cyclization of 2-acetyl-l-(2-hydroxyethyl)-5-nitropyrrole (413 414). 

Treatment of 2,3 Cpoxy-l-amines with Lewis acid induces a rearrangement to aziridinium ions that react efficiently with a nucleophiles to give functionalized hydroxy sulfides or hydroxy amines (Equation 23) <1997SL11>. Under the influence of ethylaluminium chloride, an epoxide tethered to an azide undergoes Lewis acid-assisted cyclization followed by an intramolecular Schmidt reaction and subsequent in situ reduction of the intermediate iminium species upon addition of sodium borohydride (Scheme 8). This protocol was used as a key step in a novel synthesis of indolizidine alkaloids of pharmaceutical interest <20030L583, 2004JOC3093>. 

---