1.3- Dipolar cycloaddition reactions, solvent

Most ozonolysis reaction products are postulated to form by the reaction of the 1,3-zwitterion with the extmded carbonyl compound in a 1,3-dipolar cycloaddition reaction to produce stable 1,2,4-trioxanes (ozonides) (17) as shown with itself (dimerization) to form cycHc diperoxides (4) or with protic solvents, such as alcohols, carboxyUc acids, etc, to form a-substituted alkyl hydroperoxides. The latter can form other peroxidic products, depending on reactants, reaction conditions, and solvent. 

In an extension of this work Scheeren et al. studied a series of derivatives of N-to-syl-oxazaborolidinones as catalysts for the 1,3-dipolar cycloaddition reaction of 1 with 2b [29]. The addition of a co-solvent appeared to be of major importance. Catalyst 3b was synthesized from the corresponding amino acid and BH3-THF, hence, THF was present as a co-solvent. In this reaction (-)-4b was obtained with 62% ee. If the catalyst instead was synthesized from the amino acid and... 

Despite the lack of success in the attempts at intramolecular cycloaddition with substrates 83 and 91, a moderately promising outcome was observed for the nitroalkene substrate (98, Scheme 1.10c). Heating a dilute solution of oxido-pyridinium betaine 98 in toluene to 120 °C produced a 20 % conversion to a 4 1 mixture of two cycloadducts (110 and 112), in which the major cycloadduct was identified as 110. While initially very encouraging, it became apparent that the dipolar cycloaddition reaction proceeded to no greater than 20 % conversion, an outcome independent of choice of reaction solvent. Further investigation, however, revealed that the reaction had reached thermodynamic equilibrium at 20 % conversion, a fact verified by resubmission of the purified major cycloadduct 110 to the reaction conditions to reestablish the same equilibrium mixture at 20 % conversion. 

Related to the nitrile oxide cycloadditions presented in Scheme 6.206 are 1,3-dipolar cycloaddition reactions of nitrones with alkenes leading to isoxazolidines. The group of Comes-Franchini has described cycloadditions of (Z)-a-phenyl-N-methylnitrone with allylic fluorides leading to enantiopure fluorine-containing isoxazolidines, and ultimately to amino polyols (Scheme 6.207) [374]. The reactions were carried out under solvent-free conditions in the presence of 5 mol% of either scandium(III) or indium(III) triflate. In the racemic series, an optimized 74% yield of an exo/endo mixture of cycloadducts was obtained within 15 min at 100 °C. In the case of the enantiopure allyl fluoride, a similar product distribution was achieved after 25 min at 100 °C. Reduction of the isoxazolidine cycloadducts with lithium aluminum hydride provided fluorinated enantiopure polyols of pharmaceutical interest possessing four stereocenters. 

The approach precludes the usage of volatile organic solvents, is relatively much faster, efficient, and eco-friendly. Significant rate enhancements are reported in the 1,3-dipolar cycloaddition reactions including the use of covalently grafted dipolaro-philes on the ionic liquids [189]. 

Accordingly, many reactions can be performed on the sidewalls of the CNTs, such as halogenation, hydrogenation, radical, electrophilic and nucleophilic additions, and so on [25, 37, 39, 42-44]. Exhaustively explored examples are the nitrene cycloaddition, the 1,3-dipolar cycloaddition reaction (with azomethinylides), radical additions using diazonium salts or radical addition of aromatic/phenyl primary amines. The aryl diazonium reduction can be performed by electrochemical means by forming a phenyl radical (by the extrusion of N2) that couples to a double bond [44]. Similarly, electrochemical oxidation of aromatic or aliphatic primary amines yields an amine radical that can be added to the double bond on the carbon surface. The direct covalent attachment of functional moieties to the sidewalls strongly enhances the solubility of the nanotubes in solvents and can also be tailored for different... 

Fraga-Drubreuil, J. and Cherouvrier, J.R. 2000. Clean solvent-free dipolar cycloaddition reactions assisted by focused microwave irradiations for the synthesis of new ethyl 4-cyano-2-oxazoline-4-carboxylates. Green Chemistry, 2 226-29. 

Touaux, B., Texier-Boullet, F., and Hamelin, 1.1998. Synthesis of oximes, conversion to nitrile oxides and their subsequent 1,3-dipolar cycloaddition reactions under microwave irradiation and solvent-free reaction conditions. Heteroatom Chemistry, 9 351-54. 

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... 

Addition of anionic nucleophiles to alkenes and to heteronuclear double bond systems (C=0, C=S) also lies within the scope of this Section. Chloride and cyanide ions are effieient initiators of the polymerization and copolymerization of acrylonitrile in dipolar non-HBD solvents, as reported by Parker [6], Even some 1,3-dipolar cycloaddition reactions leading to heterocyclic compounds are often better carried out in dipolar non-HBD solvents in order to increase rates and yields [311], The rate of alkaline hydrolysis of ethyl and 4-nitrophenyl acetate in dimethyl sulfoxide/water mixtures increases with increasing dimethyl sulfoxide concentration due to the increased activity of the hydroxide ion. This is presumably caused by its reduced solvation in the dipolar non-HBD solvent [312, 313]. Dimethyl sulfoxide greatly accelerates the formation of oximes from carbonyl compounds and hydroxylamine, as shown for substituted 9-oxofluorenes [314]. Nucleophilic attack on carbon disulfide by cyanide ion is possible only in A,A-dimethylformamide [315]. The fluoride ion, dissolved as tetraalkylammo-nium fluoride in dipolar difluoromethane, even reacts with carbon dioxide to yield the fluorocarbonate ion, F-C02 [840]. 

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]. 

Related to Diels-Alder [2 + 2]cycloadditions are 1,3-dipolar cycloadditions, which are known to be far less solvent-dependent cf. Eq. (5-44) in Section 5.3.3. Nagai et al [169] found that the 1,3-dipolar cycloaddition reaction of diazo-diphenylmethane to tetracyanoethene (TONE) is an exception it is 180 times faster in nonbasic trichloro-methane than in the EPD solvent 1,2-dimethoxyethane cf. Eq. (7-25). The second-order... 

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). 

Dn empirical parameter of solvent Lewis basicity, based on a 1,3-dipolar cycloaddition reaction (Nagai et al.) ... 

Ru(Tp)(L) 2( x-N2)][PF6]2 and [Ru(Tp)(methacrolein)(L)][PF6] are catalysts for the solvent-free regio and enantioselective Diels-Alder reactions between methacrolein and Cp or Cp. [ Ru(Tp)(L) 2( x-N2)][PFg]2 also catalyzes the 1,3-dipolar cycloaddition reaction between methacrolein and benzylidenephenylamine A-oxide to yield 5-methyl-2-iV-3-diphenylisoxazolidine-5-carbaldehyde.74... 

The quaternary salts of 3-hydroxy-pyri(jines are converted by mild base into zwitterionic, organic-solvent-soluble species, for which no neutral resonance form can be drawn. These pyridinium-3-olates undergo a number of dipolar cycloaddition reactions, especially across the 2,6-positions. ... 

A very recent addition to the already powerful range of microwave cycloaddition chemistry is the development of a general procedure applying a catalyst/ionic liquid system [19]. Several studies in this area have used ionic liquids, or mixtures of ionic liquids and other solvents, as reaction media in several important microwave-heated organic syntheses [20], including Diels-Alder reactions [21, 22] and 1,3-dipolar cycloaddition reactions [23]. 

---