Urethane formation, catalyzed

The catalysts of reactions between 4,4 -diphenylmethane diisocyanate (MDI) and alcohols in N,N-dimethylformamide (DMF) by dibutylin dilaurate has been investigated. The reaction rate of the catalyzed urethane formation in DMF is proportional to the square root of dibutylin dilaurate concentration. This result differs from that of similar studies on apolar solvents. The catalysis in DMF can be explained very well by a mechanism in which a small amount of the dibutylin dilaurate dissociates into a catalytic active species. 

For the catalysis of isocyanate-alcohol reactions in apolar solvents, several mechanisms have been proposed. However, the results of the kinetic measurements in DMF could not be explained with these mechanisms. So we concluded that, in the polar solvent DMF, the mechanism of the catalyzed urethane formation differs from the published mechanisms in apolar solvents. The behavior in DMF can be explained from a mechanism in which dibutyltin dilaurate dissociates into a catalytic active species. 

From measurements at different temperatures, the activation parameters AS and Afor the uncatalyzed and the catalyzed urethane formation were calculated. 

From the pseudo-first-order rate constants ku the second-order rate constants k2 are obtained by dividing kx by the alcohol concentration. It was found that the reaction rate constant kx is proportional to the alcohol concentration (at the same catalyst concentration). Table I gives the k2 values for the reaction between methanol and MDI catalyzed by dibutyltin dilaurate at 25.1°C. A plot of the k2 values vs. the dibutyltin dilaurate concentration (Figure 2) apparently deviates from a straight line, indicating that the mechanism of the catalyzed urethane formation in DMF differs from the mechanisms observed in apolar solvents (2-6). Most workers have assumed that in apolar solvents the mechanism involves formation of a complex between alcohol and dibutyltin dilaurate or the formation of a ternary complex between alcohol, isocyanate, and catalyst. In these cases, the relation between k2 and catalyst concentration differs from the relation observed in DMF. 

For dissociation reactions in DMF, AH° and AS0 values are not known. In general, the AH0 values are between —6 and 3 kcal/mole and the AS0 values are always negative (9) (from 0 to —50 eu). When AS0 is negative, it follows that AS caf is much less negative than AS Uncat- This is important for the mechanism of the catalytic reaction. Probably the transition state of the catalyzed urethane formation in DMF is much less rigid than the transition state in the uncatalyzed urethane formation. 

Figure 6.2.4 Insertion mechanism for tin catalyzed urethane formation...

Figure 6. Proposed mechanism for the urethane formation catalyzed by organo-...

The complex, C, is converted subsequently to the urea by transfer of an amine hydrogen to the 0 or N of the isocyanate. Similar complexes have been postulated to account for amine catalysis of urethane formation. Hydrogen transfer appears to be a mechanistically diflacult step, as judged by the complex kinetics of the isocyanate-amine reaction. The reaction of phenylisocyanate with aniline, for example, is self-catalyzed by the amine and autocatalyzed by the product urea. This complicated kinetic behavior may result from formation of a six-membered cyclic complex which facilitates hydrogen transfer. 

Thus, in an optimized cyclization reaction using triethylamine, the incoming BPA-fe/s-chloroformate was very quickly converted to a mixture of cyclics and polymer of a fixed composition. When DMAP was used as a catalyst, the polymer formed was not capped and proceeded to grow over the course of the reaction. Analyzing the crude cyclics with polymer present from a triethylamine catalyzed reaction reveals that significant levels of urethanes are present. In fact, for a typical lab reaction which yielded 15% polymer, the level of urethanes detected corresponded to 1.5 urethanes/chain. It has not yet been determined whether the formation of urethanes is the cause of polymer formation or the result (i.e. the polymer may be formed first followed by conversion to urethane after the likelihood of intramolecular reaction becomes vanishingly small). Certainly, urethane formation is not the only mode of polymer formation since optimized DMAP catalyzed cyclization reactions still form significant levels of polymer. 

While the studies of Boyland and Roller and Elion and co-workers, which were conducted in vivo, do suggest that urethane has a specificity for pyrimidine biosynthesis, Kaye could not demonstrate in vitro any significant inhibition by urethane of several enzymes involved in nucleic acid metabolism. Both urethane and its A -hydroxy metabolite bear a structural resemblance to carbamyl phosphate and carbamyl-L-aspartate. The enzyme aspartate transcarbamylase begins pyrimidine biosynthesis by catalyzing the formation of carbamyl-L-aspartate from carbamyl phosphate and l-aspartate. Giri and Bhide have reported that in vivo administration of urethane decreased aspartate transcarbamylase activity of lung tissue of adult male and (to a lesser extent) female mice no in vitro inhibition could be demonstrated. 

Catalysts serve a dual purpose in one-component moisture-curing urethanes. The first purpose is to accelerate the prepolymer synthesis. The second purpose is to catalyze the curing reaction of the adhesive with moisture. The most common catalysts used to promote both prepolymer formation (NCO/OH) and later the adhesive curing reaction (NCO/H2O) are dibutyltin dilaurate and DMDEE ((tertiary amine. A stabilizer such as 2,5-pentanedione is sometimes added when tin is used, but this specific stabilizer has fallen from favor in recent years, due to toxicity concerns. DMDEE is commonly used in many one-component moisture-curing urethanes. DMDEE is one of the few tertiary amines with a low alkalinity and a low vapor pressure. The latter... 

The functionalization of SAMs via ruthenium-catalyzed cross metathesis of vinyl-terminated SAMs has been reported by Lee et al.76 to install a variety of acrylic derivatives on SAMs bearing vinyl groups on their outer surface. The major drawback of this approach is the intra-SAM metathesis which causes the formation of a mixture of surface-bound products, limiting the reproducibility of the method. The formation of urethanes by the reaction of diisocyanates77 or isothiocyanates78 with hydroxyl- and amino-terminated SAMs has been reported as well. The reaction of hydroxyl-terminated SAMs with diisocyanates, allowed the preparation of isocyanate SAMs that proved to be reactive towards amines, alcohols, and water, displaying the standard chemistry of the isocyanate groups.77... 

Three isocyanate groups can react to form a trimer or substituted isocyanurate ring. Phosphines or bases such as sodium acetate or sodium formate can catalyze this reaction. The isocyanurate ring is thermally stable, has good chemical resistance, and can enhance the resistance of a urethane adhesive to aggressive environments. 

One of the first mechanisms proposed for the tin catalyzed formation of urethane is shown in Figure 6.2.4. This mechanism involves three basic steps ... 

Polymerization in such systems is based on the reaction of isocyanate with hydroxyl groups to form the urethane linkage-OrganometaI Iic compounds (especially organotin) are often used to catalyze this reaction in commercial applications such as Reaction Injection Molding. Formation of elastomers with good mechanical properties is dependent on both reaction kinetics and development of two phase morphology. 

Acids influence the NCO/OH reaction by accelerating chain extension a little, and retarding crosslinking. If p-nitrobenzoylchloride is added to a urethane system in which active hydrogen compounds must be present, this additive has a mild catalytic effect on chain extension, no effect on allophanate formation, and a strong retarding effect on biuret formation. If water is present the reaction is strongly catalyzed. 

In summarizing, it must be realized that most of all acidic conditions to remove a synthetic peptide from its gel phase support include the possibility for undesired attacks on either protected or free peptide side functions as well as on the backbone, causing fissions and conversions also during work-up manipulations of already detached raw products. This is the case because most of the usually employed protecting principles — urethanes, esters, and ethers as well as some functional sites of a peptide such as alcoholic, thioUc, and amide side chain groups — can be involved in proton catalyzed eliminations, transesterification, transamidations, and cyclol formations, though some of these side reactions usually are rather feared under basic conditions. 

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