1.3- Dipolar cycloaddition reactions, solvent effects

As measured by the criteria of stereospecificity, regioselectivity, kinetic isotope effects, and solvent effects [117-120, 541-543], 1,3-dipolar cycloaddition reactions represent orbital symmetry-allowed [n + n s] cycloadditions, which usually follow concerted pathways Diels-Alder reactions and 1,3-dipolar cycloadditions resemble each other, as demonstrated by the small solvent effects on their bimolecular rate constants. In going from nonpolar to polar solvents, the rate constants of 1,3-dipolar cycloadditions change only by a factor of 2... 10 [120, 131-134]. 

Similarly small rate factors were obtained for 1,3-dipolar cycloadditions between diphenyl diazomethane and dimethyl fumarate [131], 2,4,6-trimethylbenzenecarbonitrile oxide and tetracyanoethene or acrylonitrile [811], phenyl azide and enamines [133], diazomethane and aromatic anils [134], azomethine imines and dimethyl acetylenedi-carboxylate [134a], diazo dimethyl malonate and diethylaminopropyne [544] or N-(l-cyclohexenyl)pyrrolidine [545], and A-methyl-C-phenylnitrone and thioketones [812]. Huisgen has written comprehensive reviews on solvent polarity and rates of 1,3-dipolar cycloaddition reactions [541, 542]. The observed small solvent effects can be easily explained by the fact that the concerted, but non-synchronous, bond formation in the activated complex may lead to the destruction or creation of partial charges, connected... 

Not only Diels-Alder cycloadditions but also 1,3-dipolar cycloaddition reactions can be subject to hydrophobic rate enhancements. For example, the reaction of C,N-diphenylnitrone with di-n-butyl fumarate at 65 °C to yield an isoxazolidine is about 126 times faster in water than in ethanol, while in nonaqueous solvents there is a small 10-fold rate decrease on going from n-hexane to ethanol as solvent - in agreement with an isopolar transition-state reaction [cf. Eq. (5-44) in Section 5.3.3] [858]. Because water and ethanol have comparable polarities, the rate increase in water cannot be due to a change in solvent polarity. During the activation process, the unfavourable water contacts with the two apolar reactants are reduced, resulting in the observed rate enhancement in aqueous media. Upon addition of LiCl, NaCl, and KCl (5 m) to the aqueous reaction mixture the reaction rate increases further, whereas addition of urea (2 m) leads to a rate decrease, as expected for the structure-making and structure-breaking effects of these additives on water [858]. 

Aprotic Solvents, in J. F. Coetzee and C. D. Ritchie (eds.) Solute-Solvent Interactions, Dekker, New York, London, 1969, Vol. 1, p. 219ff. [95] H. Liebig Prdparative Chemie in aprotonischen Ldsungsmitteln, Chemiker-Ztg. 95, 301 (1971). [96] E. S. Amis and J. F. Hinton Solvent Effects on Chemical Phenomena, Academic Press, New York, London, 1973, Vol. 1, p. 271ff. [97] P. K. Kadaba Role of Protic and Dipolar Aprotic Solvents in Heterocyclic Syntheses via 1,3-Dipolar Cycloaddition Reactions, Synthesis 1973, 71. [98] J. H. Hildebrand and R. L. Scott The Solubility of Nonelectrolytes, 3 ed., Reinhold, New York, 1950 Dover, New York, 1964 J. H. Hildebrand and R. L. Scott Regular Solutions, Prentice-Hall, Englewood Cliffs/New Jersey, 1962 J. H. Hildebrand, J. M. Prausnitz, and R. L. Scott Regular and Related Solutions, Van Nostrand-Reinhold, Princeton/New Jersey, 1970. [99] A. E. M. Barton Handbook of Solubility Parameters and other Cohesion Parameters, CRC Press, Boca Raton/Elorida, 1983. [100] M. R. J. Dack, Aust. J. Chem. 28, 1643 (1975). 

The theoretical principles of cycloaddition reactions are well understood and there have been many computational studies (see Pericyclic Reactions The Diels-Alder Reaction). Often the hetero-cycloaddition reaction shows similar characteristics to the carbocyclic analog, but a number of special features have been noted. In heterocyclic chemistry the cycloaddition reactions are often dipolar computational studies show that a concerted mechanism is followed in the gas phase. However, a number of studies have noted that these dipolar cycloaddition reactions become stepwise when solvent effects are included (via the reaction field method), with a consequent loss of stereospecificity." Other characteristics of hetero-cycloaddition reactions which have been studied include the endo/exo selectivity" and the regiose-lectivity (for example, [2-1-2] vs. [2-1-4])." High levels of electron correlation are generally required in order to establish these selectivities. 

A review of recent developments in 1,3-dipolar cycloaddition of nitrones with sila-, thia-, phospha-, and halo-substituted alkenes has been reported. A DFT study of solvent effects on the intermolecular 3-l-2-cycloaddition reaction of norbornadiene with 3,4-dihydroisoquinoline A(-oxide at 398.15 K indicated that the reaction proceeds via a synchronous concerted mechanism. Chiral imidazolidinone salts, in the absence of water, promote the 1,3-dipolar cycloaddition reaction of alanine-derived ketonitrones... 

Bimolecular rate constants (k p = k bs/[R]x where [R]x represents the total concentration of one of the two reactants and whose concentration is larger than that of the second reactant, S, by a factor of more than 5) for 1,3-dipolar cycloaddition reactions of benzonitrile oxide (18) with a series of Af-substituted maleim-ides (19a-19c) in micelles of nonionic surfactants, C,2Eg, C,2E23, Cj Ejo, and CigE2o, fit reasonably well to a kinetic equation similar to Equation 3.61 (Chapter 3)." The calculated values of vary from 0.30 to 0.39 for all four nonionic micelles. Nearly 3-fold micellar deceleration effects have been shown to be similar to the effect of mixed water/1-propanol solvent with [H2O] about 15 M on k pp. However, a comparison of k with k pp in such water-organic solvents does not provide detailed information about the exact nature of the reaction environment in the micellar pseudophase. Instead, it provides information about the question insofar as the micellar reaction environment is satisfactorily mimicked by such mixed water-organic solvents. 

The kinetics of 1,3-dipolar cycloaddition of phenyl azide to nor-bornene in aqueous solutions was studied (Eq. 12.67).145 As shown in Table 12.1, when the reaction was performed in organic solvents, the reaction showed very small effects of the solvent, while in highly aqueous media, significant accelerations were observed. 

The cycloaddition of diazomethane to benzalanilines does not show any pronounced solvent effect with increasing dielectric constant of the solvent, there is hardly any increase in reaction rate with the exception of protic (e.g., water, alcohols) and dipolar aprotic solvents (e.g., DMF) that produce a significant acceleration in the reaction rate.182 The protic-dipolar aprotic solvent effects are found to be dependent on the electron-withdrawing or... 

The solvent effects on the reaction outcome from 36 with 37 may be rationalized in terms of 1,2-addition to give an initial dipolar intermediate in the polar solvent, MeCN, followed by fused azetine formation and electrocyclic ring opening to afford 38. In the less polar solvent, Et20, 1,4-cycloaddition may proceed without any dipolar intermediate,... 

Concerted + n s] cycloadditions are, in principle, forbidden by orbital symmetry [90]. This restriction is bypassed when these reactions occur via zwitterions or biradicals, or by the symmetry-allowed [A + 2 ] process. Since cycloadditions proceeding through zwitterionic intermediates or dipolar activated complexes should be affected by solvent polarity, the investigation of the solvent effects on rates can be of considerable value when considering potential models for the activated complex and the reaction mechanism [91-93]. The possible solvent effects on one-step and two-step cycloaddition reactions are shown schematically in Fig. 5-6 [92] ... 

In the case of one-step cycloaddition reactions involving an activated complex with a different dipolarity than the reactants, an increase in solvent polarity should enhance the reaction rate (c/ Fig. 5-6a). However, since two-step cycloadditions are consecutive reactions, the solvent effect depends on the relative size of AGf and AGf or of AGfi and AG cf. Fig. 5-6b). If the formation of the zwitterionic intermediate is irreversible, and AG > AG, then the first step is rate-determining in all solvents. Consequently, there is a rate acceleration with increasing solvent polarity. When AG < AG, this behaviour is reversed. If ever AG x AG, then only relatively... 

In order to form the activated complex required for the formation of product D, rotational changes of the less dipolar anti-form A to the more dipolar s jn-conformer B are necessary, to give an activated complex C with more parallel bond dipoles, which is thus more dipolar and better solvated than the reactant molecule. In agreement with this explanation is the observation that the reverse refro-Diels-Alder reaction exhibits no large solvent effect, since the activated complex C is quite similar to the reactant D [807], A very subtle solvent effect has been observed in the Diels-Alder addition of methyl acrylate to cyclopentadiene [124], The polarity of the solvent determines the ratio of endo to exo product in this kinetically controlled cycloaddition reaction, as shown in Eq. (5-43). The more polar solvents favour endo addition. 

Early work on dipolar [2 + 2] cycloadditions showed that some were extremely sensitive to solvent effects. ( alitative observations for the reaction between p-methoxystyrene and TCNE showed that it was... 

For the reaction of (122) with TCNE to form (123) the rate increase in going from carbon tetrachloride as solvent to acetonitrile is about 49(X), while for the reaction of (124) with (125) to produce (126) there is only about a factor of six increase in rate for reaction in acetonitrile relative to reaction in toluene there is no spectacular solvent effect. Does the latter reaction have a fundamentally different mechanism than is operative in [2 + 2] cycloadditions of enol ethers with TCNE Are the tetramethylene intermediates of quite different dipolar character ... 

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