Hofmann Reaction Research Articles

NitropyridineS. 9*. Synthesis of substituted 3-amino-5-nitropyridines

Substituted 3-amino-5-nitropyridines have been synthesized by the Curtius, Schmidt, and Hofmann reactions.

Immobilization of Candida rugosa lipase on glutaraldehyde-activated polyester fiber and its application for hydrolysis of some vegetable oils

Candida rugosa lipase was effectively immobilized on the poly(ethylene terephthalate) grafted acrylamide (PET-g-AAm) fiber which was prepared through Hofmann reaction. The activities of the immobilized enzyme and the free enzyme were investigated in the hydrolysis reaction of olive oil in isooctane–water biphasic medium. The activities of the free and the immobilized lipases were measured at different pH values, and temperatures. The thermal stability and storage stability of them were also determined. The kinetic parameters of the free and the immobilized lipases, Km and Vmax were calculated, as well. Moreover, the application of immobilized lipase to the hydrolysis of different vegetable oils was realized. The effect of organic solvents on olive oil hydrolysis was examined and time course of the oil hydrolysis was studied. The optimum pH was shifted from 6 to 7 by immobilization of the enzyme. The maximum activity of the free and the immobilized enzymes occurred at 40 °C. It was found that the immobilized lipase stored at 4 °C retained 90% of its original activity after 60 days, whereas the free lipase stored at 4 °C retained 75% of its activity after the same period. In addition, the immobilized lipase exhibited as 0.06 U of the remaining activity even after 10 times reuses. Kinetics studies show that the corresponding values of Km and Vmax were 47.2 mg ml−1 and 48.1 U mg−1 protein for free lipase and 151.6 mg ml−1 and 10.9 U mg−1 protein for immobilized lipase. The immobilized and free enzymes showed similar behavior with respect to the different oil hydrolysis. The time course of the immobilized lipase on canola and olive oils hydrolysis used as substrate was much better than that of the free lipase. A high rate of oil hydrolysis was obtained when isooctane was used as solvent.

Conversion of urea to hydrazine: Hofmann reaction or Favorskii analogue? Exploring reaction mechanism through isotopic labeling studies

The power of isotopic substitution for the elucidation of a reaction mechanism is illustrated with reactions named after Hofmann and Favorskii. These reactions have important roles in synthetic chemistry; therefore, a wide range of experiments involving isotopic labeling or kinetic isotope effects were employed to establish their mechanistic pathways. The concepts introduced by these investigations are drawn together with an isotopic labeling study of the oxidation of urea with hypohalites. The two mechanisms proposed for this reaction have been described as a Hofmann rearrangement and a nitrogen analogue of the Favorskii rearrangement.

Rearrangements of N-ethoxycarbonylmethyl-1,2,3,4-tetrahydroquinolinium halogenalkylates effected by sodium hydride. Synthesis of 2,3,4,5-tetrahydro-1H-3-benzazepines

Quaternary salts obtained from N-alkyl-1,2,3,4-tetrahydroisoquinolines and ethyl haloacetates or diethyl bromomalonate under the action of sodium hydride in boiling 1,4-dioxane were converted into N-alkyl-N-ethoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepines in 49–60% yield. From the reaction mixture by column chromatography products of β-elimination by Hofmann reaction, 2-(N-methyl-N-ethoxycarbonylmethyl)-aminomethylstyrenes were also isolated (yield 0.6–16%).

Tandem cleavage of 2,3,5-trimethyl 7-trifluoroacetyl-1,2,3,4-tetrahydro-pyrrolo[1,2-c]pyrimidine by activated alkynes, caused by Michael addition of a tertiary nitrogen atom to a triple bond

The interaction of 7-trifluoroacetyltetrahydropyrrolo[1,2-c]pyrimidine with acetylenedicarboxylic ester (DMAD) and ethyl propiolate in acetonitrile and alcohols has been studied. It was established that DMAD splits pyrrolopyrimidine at the aminal fragment in acetonitrile and methanol with the formation of 1-H-and 2-(N-dimethoxycarbonylvinyl-N-methyl)aminoethyl-1-methoxymethyl-3-methyl-5-trifluoroacetylpyrroles. In acetonitrile ethyl propiolate splits pyrrolopyrimidine both at the aminal fragment and at the C(3)-N(2) bond (Hofmann reaction), but in ethanol only at the C(3)-N(2) bond with the formation of 2-propenylpyrroles.

Investigation of Metal Ion Removal Selectivity Properties of the Modified Polyacrylamide Hydrogels Prepared by Transamidation and Hofmann Reactions

Modified crosslinked polyacrylamides having different functional groups prepared by transamidation reaction in aqueous and non‐aqueous medium and by Hofmann reaction were used as chelating agents for removal of Cu(II), Cd(II) and Pb(II) ions from aqueous solutions at different pH values. Under non‐competitive conditions, polymers adsorbed different amounts of metal ions, depending on their functional groups and swelling abilities. The metal ion adsorption capacities of polymers changed between 0.11–1.71 mmol/g polymer. Under competitive conditions, while the polymers having mainly secondary amine groups were highly selective for Cu(II) ions (99.4%), those having mainly secondary amide and carboxylate groups have shown high selectivity towards Pb(II) ions (99.5%). The selectivity towards Cu(II) ion decreased and Pb(II) ion selectivity increased by the decrease of the pH of the solutions. The high initial adsorption rate (<10 min) suggests that the adsorption occurs mainly on the polymer surface. A regeneration procedure by treatment with dilute HCl solution showed that the modified polymers could be used several times without loss of their adsorption capacities.

Changes in the electrochemical characteristics of a bipolar membrane immersed in high concentration of alkaline solutions

The chemical stability of a commercial bipolar membrane (Neosepta BP-1, Tokuyama Co.) was examined after immersing it in concentrated NaOH solution at different temperatures, for various periods of time. The physical and electrochemical changes in the alkali-treated membranes were measured and the effects on membrane performance were investigated thoroughly by analyzing FTIR spectra, water-splitting capabilities, and current–voltage curves. The FTIR spectra showed that the quaternary ammonium groups in the anion-exchange layer (AEL) of the BP-1 membrane decomposed via the Hofmann reaction when the membranes were immersed in 5.0 M NaOH at over 40 °C, and in 2.5 M NaOH at 50 °C. In addition, the water-splitting capability of the membranes that had undergone structural change decreased. This was attributed to decreased Donnan exclusion resulting from the decomposition of functional groups in the AEL of the BP-1 membrane. The results of the current–voltage experiments were similar to those of FTIR and water-splitting capability studies. The electric resistance for water dissociation increased when the structure of the AEL changed in concentrated alkaline solution, and at high temperature. We concluded that a more stable bipolar membrane anion-exchange layer is required for use in concentrated alkaline solutions.

Solvent free vapour phase photografting of acrylamide onto poly(methyl methacrylate)

Poly(methyl methacrylate) (PMMA) sheets were surface grafted with acrylamide under reduced pressure in a solvent free vapour of acrylamide and benzophenone. The grafting was initiated with UV irradiation and no pre-treatment of PMMA by impregnation or sorption of reactants was required. Characterization of grafted samples by ESCA and contact angles showed that the nitrogen content increased with grafting time and temperature. The surface bound amide groups obtained were converted into amine groups by the Hofmann reaction and used in coupling reactions with a p-nitrophenylcarbonate terminated PEG and 4,4,4-trifluoro butyraldehyde.

The synthesis of 16-dehydropregnenolone acetate (DPA) from potato glycoalkaloids

The use of solanidine as starting material for the synthesis of steroid hormones was strongly stimulated by the possibility to isolate large amounts ( ton scale) of potato glycoalkaloids from a waste stream of the potato starch production. A procedure is available to isolate these glycoalkaloids from the potato protein fraction and after hydrolysis solanidine is set free and can be made available as alternative for diosgenine as starting material for the production of dehydropregnenolon acetate (DPA). The conversion of solanidine to DPA was first tried by reinvestigation of several known methods like oxidation with Hg(OAc)(2), the Cope reaction and the Polonovski reaction but none of these approaches were successful. The best option was to open the E,F-ring system using the Von Braun reaction. Besides the desired major E-ring opened compound also the minor F-ring opened compound was isolated. Alternatives for the hazardous Von Braun reagent BrCN were investigated but not found. Further degradation using the Hofmann reaction was successful in a Delta(16) derivative, which led to the desired triene intermediate. Finally DPA could be obtained starting from solanidine in 9 reaction steps in 30% overall yield using the known conversion to spirosolane compounds followed by conversion to DPA. Extensive research has been performed on finding shortcuts in this route but despite all our efforts, further shortening of the route from 3-acetoxysolanidine via tomatidenol to DPA could not be accomplished.

Acid‐Promoted Reactions in 1‐Hydroxy, 1‐Dimethylaminomethyl and 1‐Methylene‐4‐arylmethyl‐2,4‐dihydro‐1H‐pyrazino [2,1‐b]quinazoline‐3,6‐diones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Acid-promoted reactions in 1-hydroxy, 1-dimethylaminomethyl and 1-methylene-4-arylmethyl-2,4-dihydro-1 H-pyrazino[2,1- b]quinazoline-3,6-diones

The 1-dimethylaminomethyl or 1-methylene group of the title compounds was introduced through a Mannich or a tandem of Mannich–Hofmann reactions as the final step of a protocol that is shorter than other previously described for these precursors of N-acyliminium species. In these compounds, the acid-promoted intramolecular cyclizations of Pictet–Spengler-type were restricted to the N(2)-unsubstituted compounds, while their N(2)-methyl substituted analogues gave instead dimerization products. The cyclization was effective with 1-hydroxy-1,2-disubstituted compounds, which were obtained through addition of a Grignard reagent to 2 H,4 H-pyrazino[2,1- b]quinazoline-1,3,6-triones.

Preparation of modified polyacrylamide hydrogels and application in removal of Cu(II) ion

Modified polyacrylamide hydrogels were prepared by transamidation and Hofmann reactions using different amine compounds. Products were characterized by their amine value (AV), equilibrium degree of swelling (EDS) and FT-IR spectroscopy. In case of transamidation on crosslinked polyacrylamide (CPAAm) in aqueous media, AV increased with reaction time and temperature, but EDS decreased with time, especially for reactions at higher temperatures. On the other hand, transamidation reactions on linear polyacrylamide (LPAAm) gave products with higher AV, but quite lower EDS than aqueous media products. Hofmann reactions were carried out on CPAAm with different amounts of NaOCl in the presence of amine compounds, to yield products with higher AV and EDS compared with conventional Hofmann reactions. The products were used for removal of copper (II) ion at pH=5.5 by batch equilibrium technique. A maximum removal capacity of 2.93mmol Cu(II)/g was obtained after a regeneration cycle.

Efficient synthesis of optically active 2-amino-2'-diphenylphosphino-1,1'-binaphthyl and its derivatives

Optically active 2-amino-2'-diphenylphosphino-1,1'-binaphthyls having various functional groups, such as amino, alkoxycarbonylamino, acylamino, mono- and dialkylamino, and sulfonylamino at C2 position were prepared. The key intermediate of the above aminophosphines was 2-carbamoyl-2'-diphenylphosphinyl-1,1'-binaphthyl synthesized from optically active 2-cyano-2'-diphenylphosphinyl-1,1'-binaphthyl. The transformation of the carbamoyl group to an amino group was effected by the Hofmann reaction.Key words: aminophosphine ligand, Hofmann reaction, optically active phosphine ligand.

Reactions at the lower potential limit in aprotic medium at a platinum cathode revisited: their role in indirect electrochemical reductive degradation of polymers

Abstract Formation of hydroxyl ions when reduction of residual water occurs at the lower potential limit at a Pt cathode in a tetrabutylammonium perchlorate solution in dimethylformamide (DMF), results not only in splitting of TBA + cations via the Hofmann reaction, but also in hydrolysis of the solvent through an intermediate charged complex into dimethylamine (DMA) and a formic acid anion. These solvent hydrolysis products can play a significant role in reactions, which may occur in electrochemical organic systems. For example, such products formed by electrochemical reduction of the background solution at a Pt cathode, interact with some electrophilic compounds present in the solution. In the case of polymers, it results both in dehydrohalogenation of halogenated polyolefins (polyvinyl chloride, poly(vinylidene fluoride), etc.) and in degradation of ester bonds in polycarbonates. That is, the solvent hydrolysis products are the active agents of the indirect electrochemical reductive degradation (ECRD) of polymers. The results obtained suggest that an intermediate charged complex of an aprotic solvent (DMF, MeCN) with OH − ions plays the governing role in the indirect ECRD of halogenated polyolefins. Furthermore, this complex and the DMA which appeared due to DMF hydrolysis are the agents of an indirect ECRD of polycarbonates. Undoubtedly, the electrochemically induced hydrolysis reactions can be minimized both in the thoroughly dried solutions, which have by our CV data a lower potential limit at Pt at about −3.0 V versus SCE, in the case of cathode materials with a high hydrogen overpotential.

A Highly Convergent Synthesis of a Fibrinogen Receptor Antagonist

A practical multikilogram synthesis of 2(S)-[(p-toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl]carbonyl]amino]propionic acid pentahydrate (1), an oral fibrinogen receptor antagonist, is described. The nine-step convergent process, which afforded 1 in 37% overall yield, included pyrazole 5a and N-tosylaminoalanine 16 as key fragments. Pyrazole 5a was obtained from pyrazole-3,5-dicarboxylic acid by esterification with MeOH, alkylation/cyclization with 3-bromopropylamine, and Michael addition with 4-vinylpyridine. N-Tosylaminoalanine 16 was prepared by tosylation of asparagine, Hofmann reaction, and benzyl esterification. Saponification of pyrazole 5a, coupling of the acid with N-tosylaminoalanine 16, and Pd-catalyzed hydrogenolysis and pyridine reduction completed the synthesis.

The Effects of Magnesium-Pretreatment on the Neuromuscular Blocking Actions of Cis-atracurium in the Cat

Background : Cis-atracurium is more potent, and less likely to release histamine and has better autonomic and cardiovascular stability, compared to atracurium. It is eliminated mainly by Hofmann reaction and produces less amounts of laudanosine, the first metabolite which has the CNS stimulating property. However, drug interactions with several ions, such as magnesium that is popular in treating eclampsia have not yet to be known. Methods : Using sciatic nerve-anterior tibialis preparation in the cat, we tried to find out whether cis-atracurium has the cumulation effect by administering four consecutive 100 g/kg of cis-atracurium. After confirming that the cis-atracurium had no cumulation effect, we proceeded the dose-response study to find out the ED50, ED95 and action duration of cis-atracurium in control group(II) and magnesium-pretreated group(III). After cumulative dose -response study, in the half of the group II and III, the infusion rate to maintain 90% twitch depression at least for 20 minutes was obtained, and afterwards, the recovery index was measured after the discontinuation of infusion. In the other half of the group II and III, while maintaining 90% twitch depression at least for 20 minutes through continuous infusion of cis-atracurium, we administered the 10 g/kg of neostigmine to measure the onset time, action duration and antagonism effect of the drug. Results : The cis-atracurium did not have the cumulation effect and in group III, ED50 and ED95 were decreased significantly from 234 82 g/kg to 103 18 g/kg and from 399 123 g/kg to 173 28 g/kg, respectively, compared with group II. The action duration of cis-atracurium ED95 in group III(190 52 sec) was significantly longer than in group II(143 29 sec). The infusion rate of cis-atracurium to maintain 90% twitch depression was significantly higher in group II in the spontaneous recovery and the neostigmine-induced antagonism(6.63 2.37 and 4.47 1.58 g/kg/min), respectively. Conclusion : The cis-atracurium do not have the cumulation effect. And, the magnesium potentiates the neuromuscular blocking actions of cis-atracurium. However, it has no effect on the antagonism action of neostigmine. (Korean J Anesthesiol 1998; 35: 215∼222)

Photocrosslinkable vinylamine copolymers. I. Synthesis and photosensitivity of cinnamoylated polyvinylamine

Vinylamine copolymers prepared by the Hofmann reaction were functionalized by amidification with cinnamoyl chloride. The resulting photosensitive polymers, which are the nitrogen analogues of poly(vinylcinnamate), can be prepared with various contents of cinnamamide side groups. The polymers exhibit a marked hydrophilicity and undergo efficient crosslinking upon exposure to 250–300 nm UV light. The sensitivity S expressed in cm2·J−1 was shown to be higher for a given content, τ, in cinnamamide groups expressed in mol·g−1 when the residual vinyl amine units are in the ammonium form. The dependence of S upon τ was of the second order for the free base form of the photopolymers, but a higher order with S approximately proportional to τ3 for the hydrochloride form of the photosensitive polymers. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 2513–2520, 1997

Synthesis and applications of polyacrylamide derivatives in the wet end of papermaking (Part II. Reactive N-chloropolyacrylamide)

N-chloropolyacrylamide (N-Cl-PAM) obtained from the N-chlorination of the Hofmann reaction of polyacrylamide is easily transferred to the amino group, even with a reaction temperature as low as 0 °C. In this study we investigated how the N-chlorination of polyacrylamide with a low reaction temperature, under low alkaline conditions to avoid the N-chloroamide group forming the amino group (Hofmann reaction), obtained high conversions of the reactive N-chloroamide group. N-Cl-PAM is a highly reactive polymer that easily promotes paper strength. It reacts with the cellulose’s hydroxyl and carboxyl groups to form covalent bonds establishing a strong bond between agents and fibers. The established networks of the strengthening agents increase the quantity and quality of the hydrogen bond structures, and therefore the molecule bonding arrangement. It has better properties than anionic and cationic wet end additives for the improvement of paper strength.

The Enantiospecific Synthesis of an Isoxazoline. A RGD Mimic Platelet GPIIb/IIIa Antagonist.

A convergent, large-scale, chiral synthesis of isoxazoline 1 has been achieved in 37% overall yield and >99.6% optical purity, starting from L-asparagine and 4-cyanobenzaldehyde. Hofmann reaction of N(alpha)-n-Boc-L-asparagine with iodosobenzene diacetate provides optically pure N(alpha)-n-Boc-L-alpha,beta-diaminopropionic acid (8) in 75% yield. A process of lipase resolution-base catalyzed epimerization gives the single enantiomer 5. Reaction of acid 5 with amine 9 in the presence of thionyl chloride forms the framework of 1. A Pinner reaction of intermediate 4 in methyl acetate or anisole, followed by an amidination with ammonium acetate, gives optically pure product 1.

7-Trifluoromethyl-5-phenyl-2-oxo-(1H)-oxazolo[5,4-b]pyridine and some of its properties

The potassium salt of 7-trifluoromethyl-5-phenyl-2-oxooxazolo[5, 4-bjpyridine (IV) was prepared from 3-aminocarbonyl-4-trifluoromethyl-6 phenyl-2(1H)-pyridone by the Hofmann reaction and was converted into 3-anuno-4-trifluoromethyl-6-phenyl-2(1H)-pyridone without isolation. 1-Substituted 7-trifluoromethyl-5phenyl-2-oxooxazolo[5, 4-b]pyridines were formed by alkylation of salt IV. 6-Halogeno-7-trifluoromethyl-S phenyl-2-oxo(1H)-oxazolo[5,4-b]pyridines have been prepared.