Morpholine, kinetic studies with

The rate of the reaction of 2,4-dimethylphenol with formaldehyde and morpholine depends on the concentration of morpholine if it is present at less than twice the formaldehyde concentration, but if the formaldehyde concentration is less than half that of morpholine then the rate depends on the concentration of formaldehyde. These data suggest that di- -morpholinylmethane is an intermediate in the reaction. Di- -morpholinylmethane was shown to give essentially the same kinetics.A kinetic study of the reaction of 3-pentadecylphenol with formaldehyde and di-n-propylamine led to a similar conclusion." These results suggest that aminals and aminol ethers should take part in Mannich reactions since both can be formed reversibly in the aqueous or alcoholic media used under the more traditional reaction conditions. 

The a- and p-L-fucosyl esters of UMP and dTMP have been prepared as anomeric mixtures by treating the nucleotides with orthoester (15) in DMF. In the absence of methylenetetrahydrofolate cofactor, thymidylate synthetase has been observed to catalyse nucleophilic addition reactions at the ethynyl moiety of 5-ethynyl-2 -deoxyuridylate. On the basis of isotope effects and other kinetic studies, it has been suggested that addition of a thiol group of the enzyme at C-6 of the nucleotides results in formation of the allenic intermediate (16), followed by addition of 2-mercaptoethanol, morpholine, or other nucleophiles at the jp-hybridized carbon of the allene, and subsequent elimination of the enzyme. 

Kinetic studies of Michael addition of alicyclic secondary amines to ethyl propiolate in H2O and MeCN have demonstrated a substantial solvent effect on reactivity and transition-state structure. The amines were found to be less reactive in MeCN, although they are by 7-9 units more basic in the aprotic solvent. The reaction rates for morpholine and deuterated morpholine proved to be identical, which rules out both a stepwise mechanism in which proton transfer would occur in the RLS and a concerted mechanism in which nucleophilic attack and proton transfer would occur through a four-membered cyclic transition state. Consequently, a stepwise mechanism with proton transfer occurring after the RLS is probable. Br0nsted-type plots were found to be linear with = 0.29 and 0.51 in H2O and MeCN, respectively, indicating that bond formation is not advanced significantly in the RLS. The small value is also consistent with the absence of isotope effect. ... 

These reactions (Table 4.8) are very facile, with particularly high reactivity for the morpholine derivatives, which together with quinine (182) and brucine (183) share the tied-back quinuchdine structure, minimizing steric interactions and enhancing reactivity. The tertiary amines 182 and 183 are used as chiral catalysts in stereoselective reactions of ketenes. Kinetic studies of zwitterion formation by reaction of quinuchdine (181) with substituted phenylketenes (Eqn (4.121)) have also been reported (Table 4.9), but no isolable products are obtained from these reactions.The rate constants with quinuchdine gave a correlation with a values for the aryl... 

Ideally, the intermediates and products need to be identified if the reaction mechanisms are to be determined unambiguously. In order to establish a complete picture of the sequence of product formation, the observed or suspected intermediate species need to be studied independently to establish their breakdown pattern and thermal stability. For example, the decomposition sequence for aqueous morpholine, which is used as a pH buffer in the water/steam cycle of many power plants, was studied in this manner and found to involve two independent, complex reaction schemes (one of which yields acetic acid). Each reactive intermediate was identified and its decomposition kinetics studied independently to verify that its decomposition rate was in keeping with the projected overall mechanism for morpholine decom-... 

The reactivity and regioselectivity in the first and second substitutions steps were studied by Ibata s group141 in the reactions of 24 with 6.0 molar equivalent of morpholine and pyrrolidine, monitoring the kinetics of formation of the reaction products by NMR measurements. In the reactions with morpholine (Figure 8), the yields of 25a, 26a and 27a increased monotonously during the initial 20 h, while 1 decreases monotonously to zero recovery. The amount of 26a decreases slowly after 20 h this indicates that the second attack of morpholine proceeds slowly to give 28a and 29a, in contrast to no attack on 27a. 

Novel diene complexes of the type [Fe(T7-C5Me5)(CO)(r7 -diene)]" (37) have been synthesized and the kinetics of addition of amines to the diene ligand measured for the 1,3-cyclohexadiene complex/ A Br0nsted plot of log k vs. of amine conjugate acid has a slope of 0.3, which is much lower than that previously reported for amine addition to [Fe(CO)3(T7 -dienyl)]" cations. This was interpreted in terms of an essentially soft character for the complexed diene in (37). However, the low Br0nsted slope may arise from a saturation effect associated with the highly basic nature of the amines (morpholine, N-methylpiperazine, pyrrolidine, piperidine) employed in the more recent study. 

A kinetic analysis of the Amadori reaction of glucose with morpholine has been reported, and a study that provides further evidence for the reversibility of the Amadori reaction is covered in Chapter 9 (Section 3.8). 

The mechanism and kinetics of a novel autocatalytic degradation of A-methylmor-pholine A-oxide (70) into morpholine and formaldehyde, induced by carbenium-iminium ions (Mannich intermediates) has been explored. " The study was prompted by the observation that NMMO as an oxidant is often consumed far beyond the stoichiometric ratio, with generation of morpholine and some formaldehyde, and at a rate faster than its reaction with reductant. Decomposition of NMMO was apparently promoted by the combination of products mentioned and could also be induced by dimethyl(methylene)iminium iodide. The proposed mechanism is in Scheme 8. Addition of small amounts of base favour the abstraction of the proton from the A-methyl group but do not prevent carbenium-iminium ion formation however, larger concentrations of base terminate the reaction. The presence of only trace amounts of water is prerequisite for the protonation-deprotonation steps to proceed. 

Jones et al. (67) also prepared a wide range of water soluble ammonium dithiocarbamate salts, [NH4][S2CNR2] (Fig. 5). They result from the iifitial reaction of the amine with concentrated aqueous ammonia in ethanol, followed by later addition of carbon disulfide at low temperatures. For example, diethanolamine, HN(CH2CH20H)2, forms a yellow precipitate in 65% yield. Castro et al. (68) studied the kinetics and mechanism of the reactions of piperidine, pyrrolidine, morpholine, and benzylamine (69) with carbon disulfide in ethanol (Fig. 6). They proceed via a dithiocarbamic acid intermediate (4), which in turn yields the dithiocarbamate anion (5) upon proton loss to the amine. While for pyrrolidine, formation of the dithiocarbamic acid is rate determining and proceeds to the dithiocarbamate irreversibly, for both morpholine and benzylamine, the transformation is reversible. Further, in these cases the ethoxide anion is found to catalyze the transformations. They have also determined that pyrrolidine is 200 times more nucleophilic toward carbon disulfide than piperidine, despite the later being only slightly more basic, a feature that may relate to the irreversible nature of the formation of pyrrolidine dithiocarbamate. 

---