Formaldehyde-catalyzed dehydration

Scheme L A mechanism for the formaldehyde catalyzed dehydration of p-hydroxynitrosamines.

Compound 79 is structurally related to TIQ 80, obtained on condensation of norepinephrine with formaldehyde (164), and to TIQ 81, detected in animal tissues after exposure to acetaldehyde (165). Acid-catalyzed dehydration of TIQ 82, the N-methyl analog of TIQ 79, should lead to the iminium species 83 (166), which on two-electron oxidation or by disproportionation should give the isoquinolinium salt 84. Such reactions, if occurring in vivo, would parallel similar reactions seen with the neurotoxin MPTP in its conversions to MPDP and MPP (167) and could possibly explain the neurotoxic effects seen with 117 (168). 

Another efficient synthesis of i7-norgestrel (209) begins with the condensation of 2-ethyl-1,3-cyclopentanedione (200, R = C2H5) with methyl vinyl ketone (199), producing (201). An asymmetric, intramolecular aldol condensation of (201) that is catalyzed by (T)-(—)-prohne followed by an acid-catalyzed dehydration yields hydrindandione (202) in 97% optical purity (205). Condensation of (202) with formaldehyde and benzenesulfinic acid generates (203) in 85% yield. 

The reaction chemistry of simple organic molecules in supercritical (SC) water can be described by heterolytic (ionic) mechanisms when the ion product 1 of the SC water exceeds 10" and by homolytic (free radical) mechanisms when <<10 1 . For example, in SC water with Kw>10-11 ethanol undergoes rapid dehydration to ethylene in the presence of dilute Arrhenius acids, such as 0.01M sulfuric acid and 1.0M acetic acid. Similarly, 1,3 dioxolane undergoes very rapid and selective hydration in SC water, producing ethylene glycol and formaldehyde without catalysts. In SC methanol the decomposition of 1,3 dioxolane yields 2 methoxyethanol, il lustrating the role of the solvent medium in the heterolytic reaction mechanism. Under conditions where K klO"11 the dehydration of ethanol to ethylene is not catalyzed by Arrhenius acids. Instead, the decomposition products include a variety of hydrocarbons and carbon oxides. 

Scheme 3. Preparation of tetraphenyl-Cp by condensation of phenylacetophenone (des-oxybenzoin) and formaldehyde in a base-catalyzed reaction followed by reductive cyclization of the 1,5-diketone with zinc in acetic add and dehydration of the 1,2-diols (32,33,43). The yield is 60%. The bromide synthesis is based on Ref. (44) (yield 70%).

Condensation of phenol with formaldehyde is a base-catalyzed process in which one resonance form of the phenoxide ion attacks formaldehyde. The resulting trimethylol phenol is then crosslinked by heat, presumably by dehydration with the intermediate formation of benzylcarbocations. The resulting polymer is Bakelite. Since the cost of phenol is relatively high and... 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

Figure 1. Reaction scheme of the acid-catalyzed two-step condensation of phenol with formaldehyde (a) and isobutanal (b), and dehydration and cyclization of the primary phenol/isobutanal product (c).

CYP-catalyzed demethylenation of the methylenedioxyphenyl (1,3-benzdioxole) group in natural products and/or medicinal agents also results in quinone formation via the intermediate catechol intermediate. The mechanism (see Scheme 1) involves an initial hydroxylation at the methylene carbon followed by partitioning between demethylenation yielding a catechol intermediate and formaldehyde/formate or dehydration to a carbene (Murray, 2000). Further oxidation of the catechol generates the ort/zo-benzoquinone species. The selective serotonin reuptake inhibitor paroxetine is a classic example of a drug that undergoes this pathway (Zhao et al., 2007). As such, the mechanistic details of quinone formation with paroxetine will be discussed later (see Scheme 25). 

The typical acid catalysts used for novolak resins are sulfuric acid, sulfonic acid, oxalic acid, or occasionally phosphoric acid. Hydrochloric acid, although once widely used, has been abandoned because of the possible formation of toxic chloromethyl ether by-products. The type of acid catalyst used and reaction conditions affect resin structure and properties. For example, oxalic acid, used for resins chosen for electrical applications, decomposes into volatile by-products at elevated processing temperatures. Oxalic acid catalyzed novolaks contain small amounts (1-2% of the original formaldehyde) of benzodioxanes formed by the cyclization and dehydration of the benzyl alcohol hemiformal intermediates. 

The aldol condensation of 4-hydroxycoumarin with fonnaldehyde provides an a,p-unsaturated carbonyl compound, which then undergoes a conjugate (1,4-) addition of a second molecule of 4-hydroxycoumarin. This reaction could be catalyzed by either trace base or trace acid the acid-catalyzed reaction is shown and discussed here. The enol portion of 4-hydroxycoumarin is the nucleophile in an aldol reaction with protonated formaldehyde. The resulting product dehydrates to provide the a,p-unsaturated carbonyl compound, which, after protonation renders it a more reactive electrophile, then reacts with another nucleophilic molecule of 4-hydroxycoumarin in a conjugate addition reaction. This product, upon loss of a proton to the aqueous solvent, leads to dicoumarol. This substance is present in moldy sweet clover. It is a blood anticoagulant and its ingestion leads to the hemorrhagic sweet clover disease that kills cattle. 

Alkyl vinyl ketones were synthesized in 1906 by heating (3-chloroethyl ketones with diethylaniline [327]. A large number of syntheses have been developed since that time, but only three or four have general applicability. Most syntheses are carried out at a low pH value to minimize the base-catalyzed condensation of the vinyl ketones. However, a rather elegant synthetic route for alkyl vinyl ketones involves a base catalyzed condensation of formaldehyde with methyl or ethyl ketones, respectively. Thermal dehydration of the p-ketoalcohol intermediates in the presence of weak acid catalysts produced a,p-unsaturated ketones in 50 to 60% yields. Several variations of this procedure have been reported [328]. 

The novolac-type phenolic prepolymer was synthesized in a 1.0 L glass reactor equipped with a thermometer, reflux condenser, and stirrer. The reagents, 188 g phenol (2 mol) and 135 g formaldehyde (in 37wt.% water solution, 1.67 mol), were fed into a flask reactor. The reaction was catalyzed by adding dilute sulfuric acid solution (2g of sulfuric acid dissolved in 10 ml of water) and reacted at 100°C for 7 hr in the reactor. The reaction was continued until the prepolymer with the desired viscosity (500-2000 cps at 25°C) was obtained. At the end of the reaction, the calculated amount of NaOH (1.63g) was dispersed in 10 ml of water and added to neutralize the sulfuric acid catalyst and then stirred for an additional 30 min. The mixture was dehydrated under a pressure of 100 mm H2O at 120-130°C until the resin was clear. 

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