Cyclodextrins with cinnamates

Hydrogenation of unsaturated carboxylic acids, such as acrylic, methacryUc, maleic, fumaric, cinnamic etc. acids was studied in aqueous solutions with a RhCU/TPPTS catalyst in the presence of p-CD and permethylated P-cyclodextrin [7]. In general, cyclodextrins caused an acceleration of these reactions. It is hard to make firm conclusions with regard the nature of this effect, since the catalyst itself is rather undefined (probably a phosphine-stabilized colloidal rhodium suspension, see 3.1.2) moreover the interaction of the substrates with the cyclodextrins was not studied separately. 

Piroxicam is given by oral, rectal, intramuscular or topical administration (10-30 mg/day, maximal initial dose 40 mg/day) as the free base, as a complex with beta-cyclodextrin and as the cinnamate or pivalate. 

The effect of cyclodextrin complexation on the bromination of styrene, methyl cinnamate, phenylacetylene, and allylbenzene has been studied.27 The corresponding bromohydrin was obtained as a major product along with dibromide in the bromination... 

Czarniecki also has examined another cinnamic acid derivative (12), in an attempt to explore the relevance of our ideas about binding geometry. Since the f-butylphenyl group binds to j3-cyclodextrin in these mixed solvents about as well as a ferrocene nucleus does (4), Czarniecki examined substrate III, the p-nitrophenyl ester of cinnamic acid carrying a ra-t-butyl group. The methoxyl group is present on the substrate for synthetic simplicity. This substrate binds nicely to /3-cyclodextrin in our medium, and again an Eadie plot shows that a one-to-one complex is formed. However, the acceleration in this case is only 1200-fold compared with hydrolysis of the substrate by the same buffer, so this is approximately 600 times less effective as a sub-... 

Cyclodextrins. Cyclodextrins (CD s) form inclusion complexes with various aromatic compounds (58), including cinnamic acid (59). Complexation of the phenolic substrates of PPO by CD s might... 

To 100 ml of aqueous solution of a-cyclodextrin (1.7 x 10 mol/1) or 3-cyclodextrin (3.0 x 10 mol/1), equimolar amounts of trans-cinnamic acid in acetone (9 wt % the acid solution) were added at 40°C. After stirring for 2 h at room temperature, the resultant white precipitates were filtered and dried in vacuo. Then the dried powders were washed with Ccirbon tetrachloride to eliminate the guest molecule not included and dried qgEdn. X-ray powder diffraction and TG-DSC techniques were used to prove complex formation in the solid state. 

The solution reactions were carried out with or without cyclodextrins in (CH3)2S0, (CH3)2SO-d0 or carbon tetrachloride. The typical experimental procedure was as follows. tra/7S-Cinnamic acid (11 mg, 0.08 mmol), powdered cx-cyclodextrin complex (162 mg, contained 0.08 mmol of the acid), and 3-cyclodextrin complex (100 mg, contained 0.08 mmol of the acid) were dissolved in 0.4 ml of (CH3)2S0-d6, to which 0.1 ml of the same solvent containing bromine (0.08 mmol) was added at 25°C. At 2 h intervals, the conversion of the acid was determined by NMR spectra. Then the reaction mixtures were poured into 20 ml of 15 wt % aqueous sodium chloride soluticn, followed by extraction with diethyl ether. The products were obtained as white solid by evaporation of the ether layer and their optical rotations were measured in ethanol on a polarimeter. 

The inclusion complexes were obtained in the form of precipitates from aqueous solutions of trans-cinnamic acid and a- or 3-cyclodextrin, in 74 and 89 % yields, respectively. The acid in the complexes was determined by NMR in (CH3)2SO-d0 and the observed acid/cyclodextrin ratios were 0.5 (ot-cyclodextrin) and 1.0 (3-cyclodextrin). The X-ray powder diffraction patterns of these complexes showed that they were highly crystalline as depicted in Figure 1 and did not corresponded to those of the pure components, so should exist as inclusion complexes.9 The thermal stability of trans-cinnamic acid in the complexes was found to be higher than those of the acid itself and in its mixture with cyclodextrins, as well as reported by Uekama, et Therefore, the guest molecule should be... 

As seen from Table I, molecular size of attacking reagent affected this gas-solid reaction, trans-Cinnamic acid in the cavity of o-cyclodextrin reacted with smaller hydrogen bromide molecule but did not with bromine and chlorine with larger molecular sizes. 

In fact, at the end of the reaction of trans-cinnamic acid with chlorine under air, the sticky solid product was obtained, but with bromine no change of the solid was observed. However, when the addition of these reagents to the acid proceeded in the microcrystalline cyclodextrin matrix, there was no visual evidence of liquid phase on the crystal even in chlorination of it under microscope. 

ABSTRACT The gas-solid halogenation and hydrohalogenation using micro-crystalline cyclodextrin complexes are found to be efficient for production of the optical active halides of ethyl trans-cinnamate in moderate optical yields On exposure to HBr at 2QOC for 15-20 hr, the cinnamate in solid a- and S-cyclodextrin complexes yields ethyl R-(+)-3-bromo-3-phenylpropanoate in 46% e.e., and S-(-)-enantiomer in 31% e.e., respectively. No addition nor substitution products are obtained with HCl vapor at 0-50°C for 15-65 hr. Bromination of the B-cyclodextrin complex results in the formation of optical active ethyl erz/t/zrc>-2,3-dibromo-3-phenylpropanoate, while chlorination gives the optical active mixture of trans and cis addition products, ethyl erythro- and threo-2,3-di-chloro-3-phenylpropanoates in 60-80% yields. Mechanism of chiral induction in the present gas-solid reaction has been proposed on the basis of the crystal structure of the complex. 

Previously [3], a strong chiral induction has been found for the chlorination of methacrylic acid in the crystalline cyclodextrin complexes. This paper describes asymmetric additions of gaseous halogens and hydrogen halides to ethyl trans-cinnamate in the crystalline complexes of a- and 3-cyclodextrins. Asymmetric bromination of 5-methyl-2-(1-methylethyl)cyclohexyl cinnamate [5] and salts of trans-cinnamic acid with several chiral amines [6] has been reported, but gives low chiral transformations up to 2-16% e.e. 

A typical experimental procedure is as follows The inclusion complex (ca. 2 g or 1 mmol) or ethyl trans-cinnamate with a-cyclodextrin was exposed to gaseous hydrogen bromide (ca. 2 molar ratio) in a desiccator (ca. 600 ml) in the dark under air at 20 C, After exposure of 20 hr, the excess of the gas was removed by evacuation and the complex was dis-... 

The solid inclusion complexes were obtained as precipitates from aqueous solutions of ethyl trans-cinnamate and a- and B-cyclodextrins in 80 and 95% yields, respectively. The ester in the complexes was determined by NMR in deuterodimethyl sulfoxide, and the molar ratios of the ester to the cyclodextrins were observed as 0.5 for the a-cyclodextrin complex and 1,0 for the 3-cyclodextrin complex. The X-ray diffraction patterns of these complexes showed that they were highly crystalline as shown in Figure 1, and could not be described with those of the ester and the cyclodextrin the precipitates should have different crystal structures from those of the guest and the hosts. These inclusion complexes have been prepared, and their dissolution and thermal behavior were examined by Uekama, et al. [9], Hursthouse, et al. determined [10] the crystal structure of 3-cyclodextrin complex with ethyl trans-cinnamate and showed that the complex was composed of 1 mole of the guest and 1 mole of the host. 

Fig. 1. A change of X-ray diffraction diagrams of the inclusion complex of ethyl trans-cinnamate with a-cyclodextrin on the gas-solid bromination at 25oc, and a diagram of a mixture of a-cyclodextrin and erythro-dibromide of the ester...

No chlorination was observed in the gas-solid chlorination of ethyl trans-cinnamate included in the cavity of a-cyclodextrin at temperatures from -5 to 50 C for 20-45 hr, as shown in Table II. The chlorination of the ester gave mixtures of erythro- and t/ireo-dichlorides having optical activities, while (+)-erz/t/zro-dibromide was the only product on the bromination of the ester inclusion complex with 3-cyclodextrin (Table I). The [a] value in D line or 589 nm at 25 C cannot be found for the pure... 

Fig. 4. Structure of the ethyl trans-cinnamate included in 3-cyclodextrin (depicted with the data in Ref. [10])...

Hydrobromination of the same substrate in the a-cyclodextrin complex gave the monobromide with the opposite configuration at 46 % e.e.. This clearly shows that ethyl trans-cinnamate forms complexes with a- and 3-cyclodextrins such that the anti-addition of hydrogen bromide occurs with high but different enantioselectivities in the two cases to yield monobromide derivatives of opposite chiralities. A detailed mechanism, however, could not be described at the present time for the observed asymmetric induction in the hydrobromination and bromination of the a-cyclodextrin complex, because no crystalline or molecular structures were determined for the ester included in a-cyclodextrin. 

The optimal binding between the preformed cavity of cyclo-oligosaccharides and a substrate requires the substrate to have a particular shape. Substrates based on the cinnamic acid, adamantane, and ferrocene frameworks show rates of acylation of cyclomaltoheptaose, which correlate well with the geometric predictions from molecular models and which are up to 10 —10 fold faster than the rates of hydrolysis. Acylation rates within the cyclodextrin cavity can be increased by a... 

Pattabiraman M, Natarajan A, Kaanumalle LS, Ramamurthy V. Templating photodimerization of trans-cinnamic acids with cucurbit[8]uril and y-cyclodextrin. Org Lett 2005 7 529-32. 

The only example recorded is the gas-solid phase reaction of hydrogen bromide with a- and P-cyclodextrin complexes of ethyl trans-cinnamate to give (R)-(+)-3-bromo-3-phenyl propanoate (46% ee) and (S)-(-)-3-bromo-3-phenyl propanoate (31% ee) (Scheme 5). 

Using modified P-cyclodextrine 23, Bender et al. report a ji-cyclodextrine based artificial enzyme mimic with a catalytic triad that has catalyzed hydrolysis rates of 10 -10 faster for norbomyl cinnamate ester [21], They show that 1 mol of 23 could be used in the hydrolysis of more than 10 mol of substrate, which proves a multiple turnover of the catalyst. The proposed mechanism is shown in Fig. 7.1. This mechanism was evaluated and questioned by Zimmerman [22],... 

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