Betaine mechanism

A more serious complication for the betaine mechanism arose when it was found that oxaphosphetanes are more stable than betaines. The earliest evidence was encountered by Ramirez et al. (17), who found that certain phosphines react with two equivalents of hexafluoroacetone to give 1,3,2-dioxaphospholane derivatives 23 (Scheme 6). These compounds rearrange into unusually stable oxaphosphetanes 26 via fragmentation to 24, followed by a proton shift to generate an intermediate ylide 25 (17). Shortly thereafter, Vedejs and Snoble (18) used P nuclear magnetic resonance (NMR) methods to show that more typical Wittig reactions of nonstabilized ylides PhjP CHR also produce oxaphosphetanes and that these intermediates can be easily observed at temperatures below 0°. Since betaines did not accumulate in any of the experiments, their conversion to oxaphosphetanes could not be rate... 

Ionic mechanisms based on betaine intermediates or TS are difficult to reconcile with the absence of solvent effects on lithium-free nonstabilized ylide reactions (Table 12) or reactivity-selectivity considerations (15). Also, there is no apparent reason why the reactants should prefer to form a high-energy intermediate such as 93 when the direct conversion to a more stable oxaphosphetane 97 is possible. Orbital symmetry should not interfere with the four-center process since phosphorus can provide 3d orbitals of appropriate symmetry for a 2s - - 2s cycloaddition. Nevertheless, the betaine mechanism has persisted in the literature because there was no direct evidence against the formation of 93 as a transient intermediate until recently (229). 

The intermediacy of the betaines used in the mechanistic discussions of the Wittig reaction has been questioned and Vedejs has proposed an alternative explanation. The Wittig reaction is subject to solvent effects that indicate a nonpolar transition state for stabilized ylids.There appears to be no direct evidence for the presence of betaines, and none have been isolated. Alternatively, Vedejs and Snoble detected oxaphosphetanes as the only observable intermediates in several Wittig reactions of nonstabilized ylids, using 3Ip NMR. In more recent work, Vedejs devised a test for the betaine mechanism based on changes in phosphorus stereochemistry in the proposed intermediates (betaine vs. oxaphosphetane). The results of this test suggested that "the conventional betaine mechanism l can play at most a minor role in the Wittig reaction".Vedejs points out that the "stereochemical test does not necessarily disprove mechanisms via intermediates with lifetimes that are short compared to the time scale of bond rotation. "494... 

The threat of accidental misuse of quaternary ammonium compounds coupled with potential harmful effects to sensitive species of fish and invertebrates has prompted some concern. Industry has responded with an effort to replace the questionable compounds with those of a more environmentally friendly nature. Newer classes of quaternaries, eg, esters (206) and betaine esters (207), have been developed. These materials are more readily biodegraded. The mechanisms of antimicrobial activity and hydrolysis of these compounds have been studied (207). AppHcations as surface disinfectants, antimicrobials, and in vitro microbiocidals have also been reported. Examples of ester-type quaternaries are shown in Figure 1. 

Foam regulators such as amine oxides, alkanolamides, and betaines are present in products where high foam value is functionally or estheticaHy desirable, mainly hand-dishwashing Hquids and shampoos. In automatic dishwashing products, on the other hand, copious foam volumes interfere with the efficiency of the mechanical rotors during operation. In this type of product, a foam depressant is often present. 

In contrast to the reaction of the betaine 58 in wet diethylether, wet THF, in which the betaine is better soluble, gives the methyl isoanhydroberberilate 64 in 71% yield. The mechanism seemingly involves an unusual carbon to nitrogen acyl migration as shown in Scheme 23. Hydration and air oxidation of the betaine to the peroxide leads to the formation of an aziridine intermediate and loss of a hydroxide anion (77TL3787). 

Michael reactions and, 895 Beta-keto ester, 851 alkylation of, 859-860 cyclic, 892-893 decarboxylation of, 857, 860 Michael reactions and. 895 pKd of, 852 synthesis of, 892-893 Beta-lactam antibiotics, 824-825 Beta oxidation pathway, 1133-1137 mechanism of, 1133-1136 Beta-pleated sheet (protein), 1038 molecular model of, 1039 secondary protein structure and, 1038-1039 Betaine, 720 Bextra. structure of, 544 BHA, synthesis of, 629 BHT, synthesis of. 629 Bicycloalkane. 129 Bijvoet. J. M., 299 Bimolecular, 363... 

Although the exact mechanism of the Tschitschibabin cyclisation has not been elucidated, it is reasonable, as shown in Scheme 4, to assume a series of reversible steps from the vinylogous ylide (or methylide) to a methine and an enol-betaine intermediate and then finally an irreversible dehydration to the indolizine nucleus. The reaction might be related to the modern electrocyclic 1,5 dipolar cyclization. 

The betaine (65) can sometimes be isolated. As shown in 16-61,65 can also go to the epoxide. The evidence for this mechanism is summarized in the review by... 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

Diazadiphosphetidines (106) or (107) are also produced by the reaction of bis(2,2,3,3-tetrafluoropropyl)phosphoroisocyanatidite (101) with either benzoyl cyanide (102) or chloral (103) respectively52. The mechanism, as shown for the formation of (.106), presumably involves the unstable betaine (104) and the cyclic imino-ylid (105). 

Reaction of dimethyl acetylenedicarboxylate (DMAD) with extremely unstable mesomeric betaine 96, generated in situ from 95, gives in 30-36% yield of a 1 2 adduct, the structure of which was originally determined as 97 <1978CL1093>. However, a more recent reinvestigation based on the H and 13C NMR spectroscopy shows that the actual product is pyrazolo[l,5- ]azepine 98, formed probably by mechanism shown in Scheme 6 <1995JCM338>. 

The mechanism of salts 52 formation is yet unclear. Based on available data, we can assume that precursors of [(R3R4SiS )2S]2 anions are betaines with the +P-C-(Si-S-)xSi-S- skeleton formed due to the insertion of shortlived silathiones [R3R4Si=S] into the initial betaines 20 or to the bimolecular reaction via direction b (Scheme 23). This is indirectly indicated by the fact... 

As mentioned in Sections 1 and 3, one of the most important problems in the study of the Wittig reaction mechanism is the determination of the relative stability of betaines with the open structure and cyclic oxapho-sphetanes as intermediates. The solution to a similar problem in chemistry... 

Transition states for betaine isomerization to ylides via the intramolecular mechanism were not localized. We believe that these processes are intermolecular and involve donor solvent molecules or the second betaine molecule as a proton carrier. 

As can be seen from the data presented, the high energies of complex formation decrease sharply the endothermicity of the retro-Wittig type decomposition and, moreover, fundamentally change the reaction mechanism. As has been shown for betaines (")X-E14Me2-CH2-E15( + )Me3 (X = S, Se E14 = Si, Ge E14 = P, As), the reaction occurs as bimolecular nucleophilic substitution at the E14 atom. For silicon betaines, the transition states TS-b-pyr with pentacoordinate silicon and nearby them no deep local minima corresponding to the C-b complexes can be localized in the reaction coordinate. 

The mechanism of transmethylation was then examined. A series of deuterium-labeled methylated compounds were synthesized by du Vigneaud s group, including arsenocholine, trimethylamine, dimethyl-glycine, and dimethylthetin. Of these only betaine and dimethylthetin served as methyl donors. In 1949 Dubnoff found that choline could only act as a donor under aerobic conditions, when it was oxidized to betaine. 

The thio-Wittig reaction, like the Wittig itself, may involve (thia)phosphetane or betaine-type structures as intermediates. A combined experimental and theoretical study over a wide range of conditions and of substrates (aliphatic vs aromatic, aldehyde- vs ketone-derived) suggests a mechanistic continuity, with solvent polarity and substrate electronic effects being the main influences on the transition from one mechanism to another. ... 

Benzyne generated from 2-carboxybenzenediazonium chloride reacted with sulfur monochloiide to give dibenzothiophene 13 (8-10%) and thiantherene 14 (26-35%) (1989SUL83). A mechanism involving the addition of sulfur mono-chloride to benzyne with the formation of betaine 15 followed by the elimination of SCI2 to afford benzothiirene 16 and a further reaction with another benzyne molecule or dimerization to thianthrene 14 is given in Scheme 8. 

Mechanisms that are probably associated, respectively, with these processes are (i) the formation of betaine intermediates (306) (Fig. 3) 103,143,149,197,200 homolysis or heterolysis of the X—Z bond (304) or the X—Z bond (305) giving diradicsd (307) or dipolar (308) intermediates, (iv) 1,3-dipolar cycloaddition yielding intermediate adducts (e.g, 309), The base-catalyzed rearrangements (ii) present very interesting mechanistic problems suitable for speculation and experimental enquiry. 

DMAD, dimethyl 2-methyl-5-phenylfuran-3,4-dicarboxylate (410) is formed. It has t n suggested that the reaction proceeds through the betaine (407), which is transformed into the ylide (408) and so into the furan (410) (Scheme 64). By carrying out the reaction in benzene it was possible to isolate the ylide (408) and thereby substantiate the suggested mechanism. 

S. (E)-3-[(S -B-Phenyt-2 ppopenoxy]aarylio aoid. An oven dried, 1-L, three-necked, round-bottomed flask equipped with a mechanical stirrer, dropping funnel and reflux condenser is purged with argon and charged with 8.20 g (0.171 mol) of 50% sodium hydride in oil (Note 7) and 90 ml of anhydrous tetrahydrofuran (Note 8). To this mixture is added a solution of 19.0 g (0.143 mol) of cinnamyl alcohol (Note 9) in 180 ml of anhydrous tetrahydrofuran. The mixture is stirred for 30 min at which point 25.0 g (0.194 mol) of (E)-(carboxyvinyl)trimethylammonium betaine is added and the reaction mixture is heated at a gentle reflux for 15 hr. The cooled reaction mixture is slowly added to a mixture of 600 mL of water and 220 ml of a saturated aqueous solution of sodium chloride (Note 10). The residual... 

A. (E>-(Carhoxyvinyt)tHmethylaimonium betaine. A 1-L, three-necked, round-bottomed flask Is equipped with a mechanical stirrer, dropping funnel, and thermometer. The flask 1s charged with 25.0 g (0.255 mol) of ethyl proplolate (Note 1), 14 mL of dichlororaethane and 440 mL of water. The mixture Is cooled to 5"C (Note 2) and 90 mL (0.35 mol) of an aqueous 25% solution of trimethylamine (Note 3) Is added under vigorous stirring over a period of 30 min. The reaction temperature remains between 0 and 5°C during the addition and then is allowed to warm to 25°C for 3 hr. The... 

With isothiocyanates, 57 generally yields the isothiazolium betaines 66 (Scheme 18). However, when R is bulky an equilibrium exists with the carbodiimide 67, which gives the imidazolium betaine 68 on heating for R = /Pr or spontaneously for R = Ph. Alternative mechanisms have been discussed. 

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