Carboxylation reaction rates

The oxidation of cyclohexene in the presence of copper, cobalt and manganese carboxylates has continued to receive attention in recent years [430-441]. The stable monomeric products of reaction are largely 2-cyclohexene-l-one and 2-cyclo-hexene-l-ol with smaller amounts of cyclohexene oxide. Cyclohexenyl hydroperoxide formed by attack of dioxygen on the allylic radical produced by allylic-hydrogen abstraction, has been established to be the reaction intermediate. The product profile has been found to vary somewhat with the metal complex used. It was found [431] that with Co(II) or Mn(II) carboxylates reaction rate and selectivity to 2-cyclohexene-l-one were maximal at 46 °C. 

Equation 20 is the rate-controlling step. The reaction rate of the hydrophobes decreases in the order primary alcohols > phenols > carboxylic acids (84). With alkylphenols and carboxylates, buildup of polyadducts begins after the starting material has been completely converted to the monoadduct, reflecting the increased acid strengths of these hydrophobes over the alcohols. Polymerization continues until all ethylene oxide has reacted. Beyond formation of the monoadduct, reactivity is essentially independent of chain length. The effectiveness of ethoxylation catalysts increases with base strength. In practice, ratios of 0.005—0.05 1 mol of NaOH, KOH, or NaOCH to alcohol are frequendy used. 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

Within the wide range of phosphorus compounds described as activating agents for polyesterification reactions,2,310 triphenylphosphine dichloride and diphenylchlorophosphate (DPCP) were found to be the most effective and convenient ones. In pyridine solution, DPCP forms a A-phosphonium salt which reacts with the carboxylic acid giving the activated acyloxy A -phosphonium salt. A favorable effect of LiBr on reaction rate and molar masses has been reported and assumed to originate from the formation of a complex with the A-phosphonium salt. This decreases the electron density of the phosphorus atom... 

The synthesis of chaparrinone and other quassinoids (naturally occurring substances with antileukemic activity) is another striking example [16a-c]. The key step of synthesis was the Diels-Alder reaction between the a,/l-unsaturated ketoaldehyde 1 (Scheme 6.1) with ethyl 4-methyl-3,5-hexadienoate 2 (R = Et). In benzene, the exo adduct is prevalent but it does not have the desired stereochemistry at C-14. In water, the reaction rate nearly doubles and both the reaction yield and the endo adduct increase considerably. By using the diene acid 2 (R = H) the reaction in water is 10 times faster than in organic solvent and the diastereoselectivity and the yield are satisfactory. The best result was obtained with diene sodium carboxylate 2 (R = Na) when the reaction is conducted 2m in diene the reaction is complete in 5h and the endo adduct is 75% of the diaster-eoisomeric reaction mixture. 

Although the use of phase-transfer catalysis (PTC) for manufacturing esters has the merits of a mild reaction condition and a relatively low cost [1], PTC has its limitations, such as the low reactivity of carboxylic ion by liquid-liquid PTC [2], a slow reaction rate by solid-liquid PTC, and the difflculty of reusing the catalyst by both techniques. 

Dithiodipropionic acid was without effect on the reaction rate but the reaction went faster at high pH, suggesting the participation of species HRS" (thiolate) and RS " (thiolate carboxylate). The retardation by ferrocyanide suggests the fol-... 

One of the most important characteristics of IL is its wide temperature range for the liquid phase with no vapor pressure, so next we tested the lipase-catalyzed reaction under reduced pressure. It is known that usual methyl esters are not suitable for lipase-catalyzed transesterification as acyl donors because reverse reaction with produced methanol takes place. However, we can avoid such difficulty when the reaction is carried out under reduced pressure even if methyl esters are used as the acyl donor, because the produced methanol is removed immediately from the reaction mixture and thus the reaction equilibrium goes through to produce the desired product. To realize this idea, proper choice of the acyl donor ester was very important. The desired reaction was accomplished using methyl phenylth-ioacetate as acyl donor. Various methyl esters can also be used as acyl donor for these reactions methyl nonanoate was also recommended and efficient optical resolution was accomplished. Using our system, we demonstrated the completely recyclable use of lipase. The transesterification took place smoothly under reduced pressure at 10 Torr at 40°C when 0.5 equivalent of methyl phenylthioacetate was used as acyl donor, and we were able to obtain this compound in optically pure form. Five repetitions of this process showed no drop in the reaction rate (Fig. 4). Recently Kato reported nice additional examples of lipase-catalyzed reaction based on the same idea that CAL-B-catalyzed esterification or amidation of carboxylic acid was accomplished under reduced pressure conditions. ... 

Figure 1 compares the conversion predicted for any reduced time I = k t with the use of Keller s theory and the above values of k /k and k2/k with experimental results obtained when polyacrylamide was exposed to 0.2N NaOH at 53 C. It may be seen that the reaction slows down at large x much more than predicted by Keller s model. In fact, this decrease of the reaction rate is even more pronounced than predicted by Keller s equations for the case where a single reacted nearest neighbor completely inhibits amide hydrolysis. We believe that this discrepancy is due to the repulsion of the catalyzing hydroxyl ions from amide residues by non-neighboring carboxylate groups. 

Alternatively, esterification of carboxylic acid can be carried out in aqueous media by reacting carboxylic acid salts with alkyl halides through nucleophilic substitutions (Eq. 9.10).20 The reaction rate of alkyl halides with alkali metal salts of carboxylic acids to give esters increases with the increasing concentration of catalyst, halide, and solvent polarity and is reduced by water. Various thymyl ethers and esters can be synthesized by the reactions of thymol with alkyl halides and acid chlorides, respectively, in aqueous medium under microwave irradiation (Eq. 9.11).21 Such an esterification reaction of poly(methacrylic acid) can be performed readily with alkyl halides using DBU in aqueous solutions, although the rate of the reaction decreases with increasing water content.22... 

Due to excellent yields, mild reaction conditions, and a fast reaction rate, the azolide method is well suited to the synthesis of isotopically labeled esters, even ones with very short half-lives, just as it is always useful for the esterification of sensitive carboxylic acids, alcohols, and phenols under mild conditions. An example is provided by the synthesis of [nC]-quinuclidinyl benzilate prepared from benzilic acid, CDI, and nC-labeled quinuclidinol.[147]... 

Because of the higher reaction rate, 7V(3)-alkylimidazolium-A ( 1 )-carboxylates or thiocarboxylates have often been used for the synthesis of carbamates and thiocarbamates by the azolide method instead of imidazole-iV-carboxylates. 

To determine the rate behavior of chain growth polymerization reactions, we rely on standard chemical techniques. We can choose to follow the change in concentration of the reactive groups, such as the carboxylic acid or amine groups above, with spectroscopic or wet lab techniques. We may also choose to monitor the average molecular weight of the sample as a function of time. From these data it is possible to calculate the reaction rate, the rate constant, and the order of the reacting species. 

As recently as 1965, Thoma and Stewart predicted that alterations in reaction rates [in the presence of the cycloamyloses] should be anticipated whose magnitude and sign will fluctuate with the reaction type, and added that at the present juncture, it is impossible to sort out confidently. . . which factors may contribute importantly to raising or lowering the activation energy of the reaction. In the short interval between 1965 and the present, a wide variety of cycloamylose-induced rate accelerations and decelerations have, indeed, been revealed. More importantly, rate alterations imposed by the cycloamyloses can now be explained with substantially more confidence. The reactions of derivatives of carboxylic acids and organo-phosphorus compounds with the cycloamyloses, for example, proceed to form covalent intermediates. Other types of reactions appear to be influenced by the dielectric properties of the microscopic cycloamylose cavity. Still other reactions may be affected by the geometrical requirements of the inclusion process. 

Both CO and C02 are reduced by eh. The immediate product of the first reaction is CO-, which reacts with water, giving OH and the formyl radical the latter has been identified by pulse radiolysis. The product of carbon dioxide reduction, C02-, is stable in the condensed phase with an absorption at 260 nm. It reacts with various organic radicals in addition reactions, giving carboxylates with rates that are competitive with ion-ion or radical-radical combination rates. 

Room temperature conditions affected only the conversion, the reaction rate being smaller (entry 6). Noticeably, cyclization of 2-prop-2-ynyl-malonic acid monomethyl ester le and 2-phenyl-pent-4-ynoic acid If, also occurred with very good results (entries 7, 8). The obtained results may be ascribed to the LDH support, which exhibits enough basic properties to activate the unsubtituted acetylenic carboxylic acids. Basically, the composition of the LDH exhibits only a very minor influence in these reactions. 

Acylation reactions can be done at the nucleophilic sites on pyrimidines using activated forms of carboxylic acids. Acylation of functional groups in nucleotides typically is used for protection during synthesis (Reese, 1973). However, for bioconjugate applications, the reactivity of native groups on pyrimidines is not as great as that obtained using an amine-terminal spacer derivative, such as those described in Chapter 27, Section 2.1. Yields and reaction rates are typically low for direct acylation or alkylation of pyrimidine bases, especially in aqueous environments. 

Derivatives of hydrazine, especially the hydrazide compounds formed from carboxylate groups, can react specifically with aldehyde or ketone functional groups in target molecules. Reaction with either group creates a hydrazone linkage (Reaction 44)—a type of Schiff base. This bond is relatively stable if it is formed with a ketone, but somewhat labile if the reaction is with an aldehyde group. However, the reaction rate of hydrazine derivatives with aldehydes typically is faster than the rate with ketones. Hydrazone formation with aldehydes, however, results in much more stable bonds than the easily reversible Schiff base interaction of an amine with an aldehyde. To further stabilize the bond between a hydrazide and an aldehyde, the hydrazone may be reacted with sodium cyanoborohydride to reduce the double bond and form a secure covalent linkage. 

Wash particles (e.g., 100 mg of 1 pm carboxylated latex beads) into coupling buffer (i.e., 50 mM MES, pH 6.0 or 50 mM sodium phosphate, pH 7.2 buffers with pH values from pH 4.5 -7.5 may be used with success however, as the pH increases the reaction rate will decrease). Suspend the particles in 5 ml coupling buffer. The addition of a dilute detergent solution may be done to increase particle stability (e.g., final concentration of 0.01 percent sodium dodecyl sulfate (SDS)). Avoid the addition of any components containing carboxylates or amines (such as acetate, glycine, Tris, imidazole, etc.). Also, avoid the presence of thiols (e.g., dithiothreitol (DTT), 2-mercaptoethanol, etc.), as these will react with EDC and effectively inactivate it. 

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