1,3-dipolar cycloaddition reactions interaction

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Frontier-orbital Interactions for 1,3-Dipolar Cycloaddition Reactions of Nitrones... 

The typical 1,3-dipolar cycloaddition reaction of nitrones with alkenes involves a dominant interaction of HOMO (nitrone) and LUMO (alkenes). The inverse-electron demand of the... 

Reactivity of diazo compounds towards 1,3-dipolar cycloaddition reactions with 1 -[1,2,3]-, 2H-[1,2,3]-, [1,3,2]-, and [l,2,4]diazaphospholes has been rationalized by FMO approach using DFT calculations [107], In most of the cases, HOMODipole-LUMOn. . .. interaction has been found to control the reactivity and among... 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

Studies from our laboratories by Pantarotto et al. (2004a, b), Wu et al. (2005) and Kostarelos et al. (2007) using covalently functionalised CNTs (1,3-dipolar cycloaddition reaction chemistry) have reproducibly described that CNTs were uptaken by cells via pathways other than endocytosis. This work has experimentally observed that CNTs were able to interact with plasma membranes and cross into the cytoplasm without the apparent need of engulfment into a cellular compartment... 

The structural requirements of the mesomeric betaines described in Section III endow these molecules with reactive -electron systems whose orbital symmetries are suitable for participation in a variety of pericyclic reactions. In particular, many betaines undergo 1,3-dipolar cycloaddition reactions giving stable adducts. Since these reactions are moderately exothermic, the transition state can be expected to occur early in the reaction and the magnitude of the frontier orbital interactions, as 1,3-dipole and 1,3-dipolarophile approach, can be expected to influence the energy of the transition state—and therefore the reaction rate and the structure of the product. This is the essence of frontier molecular orbital (EMO) theory, several accounts of which have been published. 16.317 application of the FMO method to the pericyclic reactions of mesomeric betaines has met with considerable success. The following section describes how the reactivity, electroselectivity, and regioselectivity of these molecules have been rationalized. 

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 structural requirements of the mesomeric betaines described in Section III endow these molecules with reactive -electron systems whose orbital symmetries are suitable for participation in a variety of pericyclic reactions. In particular, many betaines undergo 1,3-dipolar cycloaddition reactions giving stable adducts. Since these reactions are moderately exothermic, the transition state can be expected to occur early in the reaction and the magnitude of the frontier orbital interactions, as 1,3-dipole and... 

Dipolar cycloaddition reactions are generally classified into three types, dipole HO controlled, dipole LU controlled or HO,LU controlled, depending upon the relative energies of the dipole and dipolarophile frontier molecular orbitals. If the energy gap separating the dipole HOMO from the dipolarophile LUMO is smaller than that between the dipole LUMO and the dipolarophile HOMO, then the reaction is said to be dipole HO controlled. If the dipole LUMO-dipolarophile HOMO energy gap is smaller, then dipole LU control prevails. If the energy difference between the dipole HOMO and the dipolarophile LUMO is about the same as that between the dipole LUMO and the dipolarophile HOMO, dien neither interaction dominates and HO,LU control is operable. 

Fig. 10.16. Prediction of the regioselectivity of 1,3-dipolar cycloaddition reactions on the basis of FMO interactions. The orbital energies of the reactants (in eV) are indicated.

Upon heating, aziridine 191 opened in the conrotatory manner to give azomethine yhdes 192 and/or 193, which underwent 1,3-dipolar cycloaddition reactions with alkenes and acetylenes. With styrene, for example, pyrrolidine 194 was formed exclusively in 81 % yield, and the regiochemistry of the cycloaddition was ascribed to control by the LUMO of the electron-deficient azomethine ylide. The cis relationship of the phenyl and benzoyl groups was attributed to secondary orbital interactions between them in the transition state. 

In behaviour that is typical of a 1,3-dipolar cycloaddition reaction, OSO4 reacts almost as well with electron-poor as with electron-rich alkenes. OSO4 simply chooses to attack the alk-ene HOMO or its LUMO, depending on which gives the best interaction. This is quite different from the electrophilic addition of m-CPBA or Br2 to alkenes. 

Dipolarophiles which contain an electron-deficient substituent undergo smooth cycloaddition reactions with nitrile ylides. The relative reactivity of the nitrile ylide toward a series of dipolarophiles is determined primarily by the extent of stabilization afforded the transition state by interaction of the dipole highest-occupied (HO) and dipolarophile lowest-unoccupied (LU) orbitals. Substituents which lower the dipolarophile LU energy accelerate the 1,3-dipolar cycloaddition reaction. For example, fumaronitrile undergoes cycloaddition at a rate which is 189,000 times faster than methyl crotonate. Ordinary olefins react so sluggishly that their bimolecular rate constants cannot be measured. 

The interaction of the capsnle with the diazoacetate esters did not lead to their decomposition. In fact, aU snbstrates remained nnaltered both in the presence and in the absence of the capsnle, even at 50°C for 20 h in water saturated chloroform-d. More interestingly, since this class of molecules are good partners for the 1,3-dipolar cycloaddition reactions with a large series of dipolarophiles [60], their interaction with electron-poor alkenes was investigated in the presence and in the absence of the capsule in order to ascertain its snpramolecular catalytic effects. 

The transition state of the concerted 1,3-dipolar cycloaddition reaction is controlled by the frontier molecular orbitals of the substrates. Hence, the reaction of dipoles with dipolarophiles involves either a LUMO-dipole/ HOMO-dipolarophile reaction or a HOMO-dipole/LUMO-dipolarophile interaction, depending on the nature of the dipole and the dipolarophile. 

F. 3.11 Frontier orbital interactions in a 1,3-dipolar cycloaddition reaction... 

Dipolar cycloaddition reactions of diazoalkanes with dipolarophiles leading to various heterocycles have been well studied in recent decades [13]. In this section we highlight mainly some recent advances in transition-metal-mediated 1,3-dipolar cycloaddition reactions of diazoalkanes for the construction of pyrazoles, where transition metals are usually utilized as promoters to narrow the energy gap between the two reacting components HOMOdipoiarophiie-LUMOdipoie and/or LUMOdipoiarophiie-HOMOdipoie interactions. 

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