Cyclisation reactions in solution

Relative rates and approximate cyclisation constants C for the cyclisation of 

Approximate cyclisation constants Cfor the lactonisation of HO(CH2) 2 C02H  

Another important investigation of a quantitative nature of the pre-war era is that of Ziegler et al. (1937), who studied the kinetics of the base-promoted cyclisation of o-((o-bromoalkoxy)phenols (43) in ethanol solution 

Approximate relative rates of cyclisation of o-bromoalkoxyphenoxides [1] to catechol polymethylene ethers [2] in ethanol  

during the last decade, considerable advances have been made towards a quantitative understanding of the structural and energetic factors controlling chain cyclisation. Thanks to the application of modern technology there has been a substantial accumulation of reliable data in the form of accurate kinetic or equilibrium measurements of cyclisation reactions of bifunctional chains, as well as of careful analyses of ring-chain polymerisation equilibria. These will be dealt with in the remaining part of this section. 

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Cyclisation of polymer chains. Theory and experiment 64 Entropy changes for cyclisation reactions in solution 74... 

Given that the first approximation for solvent interactions seems adequate to a reasonable degree of accuracy, with the possible exception of some of the very short-chain compounds, we can now attempt an extension to available entropy changes for cyclisation reactions in solution of the same treatment as was applied in the preceding section to entropy changes for hypothetical cyclisation reactions in the gas phase. 

Since gas-phase reactions are free from complications arising from solvation effects, a convenient starting point for a meaningful analysis of structural effects on reactivity would be the study of cyclisation reactions in the gas phase. Unfortunately, quantitative evidence of this sort is scanty. A section in Winnik s review (Winnik, 1981a) is devoted to cyclisation and the gas-phase conformation of hydrocarbon chains. From the numerous references therein one obtains a substantial body of evidence pointing to a general resemblance of cyclisation reactions in the gas phase with cyclisation reactions in solution. However, as Winnik has pointed out, gas-phase reactions have not been studied so far with the same kind of detail that is possible for reactions in solution. As a result, any attempt at understanding the relations between structure and reactivity in the area of cyclisation reactions must still rely heavily upon solution chemistry data. 

In an earlier report, the microwave-mediated intramolecular carbanilide cyclisation to hydantoins was described44. Since the hydantoin moiety imparts a broad range of biological activities, several protocols involving both reactions in solution and on solid-phase have been investigated. Within this report, the first microwave-assisted synthetic approach to hydantoins is described (Scheme 7.36). 

Finally, there is a large body of experimental and theoretical contributions from investigators who are mainly interested in the dynamic and conformational properties of chain molecules. The basic idea is that the cyclisation probability of a chain is related to the mean separation of the chain ends (Morawetz, 1975). Up to date comprehensive review articles are available on the subject (Semiyen, 1976 Winnik, 1977, 1981a Imanishi, 1979). Rates and equilibria of the chemical reactions occurring between functional groups attached to the ends or to the interior of a flexible chain molecule are believed to provide a convenient testing ground for theories of chain conformations and chain dynamics in solution. 

Early interest in the relation between the shape of chain molecules and solvent in ring-closure reactions can be traced in the work of Salomon (1936a). More recently, the problem has been given much attention by Winnik (1977). Though being small (see p. 64), the corresponding effects on the ease of cyclisation are believed to be of considerable importance in probing the shape of hydrocarbon and other flexible chains in solution. 

In most cases the ring opening goes to completion and there are very few examples of the reverse reaction i.e., the thermal cyclisation of butadienes. The ring opening takes place smoothly in solution or in the gas phase at temperatures between 120° and 200°C. 

As Skinner has pointed out [7], there is no evidence for the existence of BFyH20 in the gas phase at ordinary temperatures, and the solid monohydrate of BF3 owes its stability to the lattice energy thus D(BF3 - OH2) must be very small. The calculation of AH2 shows that even if BFyH20 could exist in solution as isolated molecules at low temperatures, reaction (3) would not take place. We conclude therefore that proton transfer to the complex anion cannot occur in this system and that there is probably no true termination except by impurities. The only termination reactions which have been definitely established in cationic polymerisations have been described before [2, 8], and cannot at present be discussed profitably in terms of their energetics. It should be noted, however, that in systems such as styrene-S C/4 the smaller proton affinity of the dead (unsaturated or cyclised) polymer, coupled, with the greater size of the anion and smaller size of the cation may make AHX much less positive so that reaction (2) may then be possible because AG° 0. This would mean that the equilibrium between initiation and termination is in an intermediate position. 

Priebe et al. [79] investigated the chemical stabiHty of iodixanol under accelerating cleavage of the central bridge under ultraviolet irradiation by a Norrish Type-II reaction. Basic conditions (pH 14) combined with heat (60 °C) initiated a cyclisation reaction. On the other hand, less than 1 % iodixanol decomposed in solution heated to 140 °C for 2 days or under both basic conditions (pH 11,20°C, 5 days) and acidic conditions (pH 0.4,80 °C, 5 days) or under an oxygen atmosphere (100°C,3 days). 

Aspartame is relatively unstable in solution, undergoing cyclisation by intramolecular self-aminolysis at pH values in excess of 2.0 [91]. This follows nucleophilic attack of the free base N-terminal amino group on the phenylalanine carboxyl group resulting in the formation of 3-methylenecarboxyl-6-benzyl-2, 5-diketopiperazine (DKP). The DKP further hydrolyses to L-aspartyl-L-phenyl-alanine and to L-phenylalanine-L-aspartate [92]. Grant and co-workers [93] have extensively investigated the solid-state stability of aspartame. At elevated temperatures, dehydration followed by loss of methanol and the resultant cyclisation to DKP were observed. The solid-state reaction mechanism was described as Prout-Tompkins kinetics (via nucleation control mechanism). 

The final step in the synthesis ofthe pyridopyrimidinones (Scheme 7.10a) involved the release of the products from the solid support by intramolecular cyclisation, whereupon the pure products were obtained in solution. All reaction steps were carried out in a dedicated single-mode microwave instrument under sealed vessel conditions. 

The ingenious solution was to isomerise the alkene and cyclise it in a single operation using light to catalyse both reactions. Cyclisation of Z-18 should give trans-27 by a conrotatory electrocyclic reaction but the reaction was conducted with diphenyldiselenide PhSe-SePh which oxidised it to the benzene 28 in the reaction mixture. So three steps were combined in one. 

Bach T, Aechtner T, Neumtiller B (2002b) Enantioselective Norrish-Yang cyclisation reactions of A-( )-oxo-a>-phenylaIkyl)-substituted imidazolidin-ones in solution and in the solid state. Chem Eur J 8 2464-2475 Bach T, Grosch B, Strassner T, Herdtweck E (2003) Enantioselective [6jt]-photocyclisation reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation. J Org Chem 68 1107-1116... 

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