Nitrosation Of Secondary Amines Research Articles

Cover Feature: Flow Electrochemistry for the N‐Nitrosation of Secondary Amines (Chem. Eur. J. 32/2023)

Electrochemistry is a valuable tool used by modern synthetic chemists who use electricity to facilitate redox reactions. In this image, created by Karrar Nadhom, the dragon provides the electrical surge to create a reaction between sodium nitrite and a secondary amine, which are fused to form the N-nitroso product. Despite dragons being extinct in most parts of the world, the title reaction is an ecologically green process, as indicated by the colour of the dragon. More information can be found in the Research Article by T. Wirth and co-workers (DOI: 10.1002/chem.202300957).

The Use of Potassium/Sodium Nitrite as a Nitrosating Agent in the Electrooxidative N‐Nitrosation of Secondary Amines

AbstractWe report herein on the electrochemical N‐nitrosation of secondary amines using widely available sodium/potassium nitrite as a nitrosating agent. This approach not only eliminates the need for using a combination of sodium/potassium and a strong acid but also has good functional group tolerance. The reaction is compatible with the late‐stage modification of pharmaceutical compounds and could be conducted in gram scale with a high reaction efficiency. Preliminary mechanistic studies indicate that the N‐nitrosation occurs via the anodic oxidation of KNO2 into an NO2 radical which is then transformed into an NO+ cation.

Nitrozamini - karcinogeni hemijski "uljezi" u radnoj sredini

Nitrosamines, or more precisely N-nitrosamines, along with N-nitrosamides, belongs to N-nitroso compounds, a class of organic compounds that have a nitroso (-N=O) group attached directly to a nitrogen atom. Only a few of them occur naturally while the majority is formed by nitrosation of secondary amines in a living and working environment, food, tobacco smoke, etc. These compounds have scarce application in the industry, but they can be formed in situ, so they can be considered as chemical intruders in working environments. Considering their toxicity, especially carcinogenicity, where there is a risk of exposure to N-nitroso compounds, appropriate protection measures should be taken, including process control, work practices, protective clothing, use of respirators, legal regulations.

N‐Nitrosation of Secondary Amines Using Supported Perchloric Acid on Silica Gel and Stereoselectivity Study of Nitrosated Products

AbstractN‐Nitrosation of different types of secondary amines has been proceeded using supported perchloric acid on silica gel and sodiume nitrite under heterogeneous conditions. The operational system is simple and high pure products can be easily isolated with good to high yields.

P58: Secondary amines containing one aromatic nitro group: Preparation, nitrosation, sustained nitric oxide release, and the synergistic effects of released nitric oxide and an arginase inhibitor on vascular smooth muscle cell proliferation

Background Nitric oxide (NO) is synthesized by vascular endothelial cells in vivo from l -arginine by nitric oxide synthases (NOS). Initial events in the onset of atherosclerosis lead to endothelial dysfunction and subsequent decrease of endogenous NO. Within the vasculature NO inhibits smooth muscle cell proliferation (SMC), therefore decreased concentrations lead to rapid SMC division, a key event in the formation of atherosclerotic plaques. Reestablishing physiological levels exogenously with NO-donors, aims to stop uncontrolled SMC proliferation and the progression of atherosclerosis. However current NO donors rapidly release NO in highly concentrated, single bursts, leading to cellular oxidative stress. In contrast, N-nitroso (N–NO) NO donors synthesized in our lab through the nitrosation of secondary amines, release NO in a slow, sustained manner, establishing and maintaining low NO concentrations that effectively reduce SMC proliferation, without onset of oxidative stress.Additionally, NOS competes for l -arginine with arginase, which catalyzes its conversion to l -ornithine, the precursor to various polyamines-known stimulators of SMC proliferation. Arginase inhibition would reduce SMC proliferation by decreasing l -ornithine concentrations and providing increased l -arginine for endogenous NO production. Combining arginase inhibition with NO-donor application may prevent SMC proliferation more effectively than either method individually, and may have a synergistic effect. Methods Two isomeric families of NO-donors, prepared in our laboratory, were applied to SMC cultures at various concentrations. Each secondary amine precursor was also tested for any toxic or anti-proliferative effects. Likewise the potent arginase inhibitor, ABH was tested to determine the most effective concentration for proliferation reduction. Finally, optimized concentrations of NO-donors and ABH were added in tandem. Proliferation and toxicity were monitored using a cell viability and LIVE/DEAD assay. A third assay was implemented to monitor changes in intracellular NO concentrations due to the addition of each compound. Results Cellular viability assays showed eight of ten amines exerted no toxic or anti-proliferative effects in the range tested (0.1–20 μM), nor did they increase intracellular NO concentrations. These compounds were nitrosated and tested in same concentration range. All donors exhibited proliferation inhibition without inducing cell death between 5% and 20 μM in a concentration dependent manner. At 20 μM, the decrease in viable cells ranged from 5% to 22%. Likewise, ABH decreased the number of viable cells in a concentration dependent manner from 0.001 to 5.0 mM by 9.9–30.0%, respectively. Both the NO-donors and ABH increased intracellular NO with increasing concentrations. Finally, the most effective NO-donor from each family (20 μM) in combination with ABH (5 mM) inhibited SMC proliferation in a synergistic manner, reducing the number of viable cells by an additional 2% and 16% compared to the sum of individual components alone. These results were supported by the synergistic increase of intracellular NO. Conclusion Inhibition of SMC proliferation after endothelial dysfunction could slow down the establishment of arterial plaques, reducing the occurrence of cardiovascular diseases including atherosclerosis. Reestablishing NO concentrations both exogenously with NO-donors and endogenously by arginase inhibition with ABH simultaneously has shown to more effectively reduce SMC proliferation than either method individually, while avoiding onset of oxidative stress. Disclosure NIH, Award # R15HL 106600.

Ionic liquid 1-(4-nitritobutyl)-3-methylimidazolium chloride as a new reagent for the efficient N-nitrosation of secondary amines under mild conditions

1-(4-Nitritobutyl)-3-methylimidazolium chloride has been developed as a new reagent for efficient nitrosation of secondary amines at 0 °C to room temperature. A variety of N-nitrosamines were prepared in excellent yields by use of this task-specific ionic liquid under mild and heterogeneous conditions.

ChemInform Abstract: An Efficient Method for N-Nitrosation of Secondary Amines under Mild and Heterogeneous Conditions.

Abstract A combination of inorganic acidic salts or silica gel supported inorganic acids and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso drivatives under mild and heterogeneous conditions in moderate to excellent yields. Mg(HSO4)2 and NaHSO4 are superior to all the aforementioned reagents in convenience, yield and purity of the isolated nitrosoamines.

Molybdate Sulfuric Acid/NaNO2: A Novel Heterogeneous System for the N‐Nitrosation of Secondary Amines under Mild Conditions

AbstractWet molybdate sulfuric acid (= dioxo[bis(sulfato‐κO)]molybdenum; MSA), a new solid acid, can be used in combination with sodium nitrite (NaNO2) to transform a variety of secondary amines to the corresponding N‐nitroso compounds under mild, heterogeneous conditions (Table). The process has several advantages: the reagents are inexpensive and non‐hazardous, the reaction is clean, fast, and high‐yielding, and MSA can be readily removed by filtration and re‐used (after treatment with HCl) without loss of activity. Further, only N‐nitrosation was observed, but no C‐ or O‐nitrosation.

Alumina–Methanesulfonic Acid (AMA)/NaNO2 as an Efficient Procedure for the Chemoselectivite N‐Nitrosation of Secondary Amines

A combination of alumina/methanesulfonic acid (AMA) and sodium nitrite was used as an effective nitrosating agent for the nitrosation of secondary amines under mild and heterogeneous conditions in good to excellent yields.

N-NITROSATION OF SECONDARY AMINES UNDER MILD AND HETEROGENEOUS CONDITIONS

A combination of potassium monopersulfate and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in excellent yields.

Chemoselective N-nitrosation of secondary amines under mild and heterogeneous conditions via in situ generation of NOCl

A combination of inorganic chloride salts [e.g. WCl6, AlCl3 and ZnCl2] and sodium nitrite in the presence of wet SiO2 were used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.

An Efficient Method for N-Nitrosation of Secondary Amines Under Mild and Heterogeneous Conditions

A combination of inorganic acidic salts or silica gel supported inorganic acids and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso drivatives under mild and heterogeneous conditions in moderate to excellent yields. Mg(HSO4)2 and NaHSO4 are superior to all the aforementioned reagents in convenience, yield and purity of the isolated nitrosoamines.

Simplification of Colorimetric Measurement of Secondary Amines by Nitrosation

We studied the simplification of the usual colorimetric measurement of secondary amines, using nitrosation of secondary amines with KNO2, degradation of KNO2 with sulfamic acid, extraction of nitrosamines with CH2Cl2, and coloring of the nitrosamines. To skip the most time-consuming CH2Cl2 extraction step, the KNO2 concentration for nitrosation was reduced from 60% to 400 mM. This modification enabled us not only to measure secondary amines more quickly and easily, but also to measure secondary amines yielding nitrosamines hardly extractable with CH2Cl2.

Effects of ergothioneine, cysteine, and glutathione on nitrosation of secondary amines under physiologic conditions.

The effects of ergothioneine, cysteine, and glutathione, which are naturally occurring sulfhydryl compounds, on the aerobic and anaerobic nitrosation of dimethylamine were studied at pH 2.0-7.0 and at 37 degrees C. Under aerobic conditions, ergothioneine increased the formation of dimethylnitrosamine (DMN) at all pH values tested, cysteine and glutathione had the same effect at pH 4.0-6.0, and cysteine formed DMN at pH 7.0. However, as compared to controls cysteine showed no increased effect in an O2 atmosphere at pH 6.0. The effects of sulfhydryl compounds on anaerobic nitrosation were more significant (p < 0.001) than on aerobic nitrosation, probably because these sulfhydryl compounds, except ergothioneine, are easily oxidized. Ergothioneine increased aerobic nitrosation almost as strongly as anaerobic nitrosation. The effects of sulfhydryl compounds, especially ergothioneine, on nitrosation at physiologic pH and temperature might be significant in the in vivo formation of N-nitrosamines in the hemorrhage or ulcerous gastrointestinal tract or injured organs.

Studies on the formation of nitrosamines. VIII. The effects of ethanol, glucose and sucrose on nitrosation of secondary amines following alkalization of reaction mixture.

When diethylamine (DEA) was reacted with sodium nitrite at pH 3 in the presence and absence of ethanol, glucose or sucrose, followed by alkalization with sodium hydroxide to terminate the reaction, nitrosodiethylamine (NDEA) formation was stimulated by the addition of ethanol, glucose or sucrose. However, these compounds had no effect on NDEA formation when the reaction was terminated by the addition of sulfamic acid. Further, when the mixed solution of sodium nitrite and ethanol, glucose or sucrose was first acidified to pH 3, next alkalized to pH 13, and then combined with DEA, NDEA was formed in proportion to the concentration of ethanol, glucose or sucrose. NDEA was also formed in the reaction of DEA and ethylnitrite in basic medium. It can be probably postulated that the corresponding nitrous acid ester is formed from sodium nitrite and ethanol, glucose or sucrose in acidic medium and nitrosates DEA in alkaline medium. It should be noted that apparent stimulation occurs in nitrosation of secondary amines in the presence of compounds having alcoholic hydroxyl groups when reaction is terminated by alkalization.

Catalytic effect of mitrosophenols on N-nitrosamine formation.

THE effect of phenolic compounds on the rate of nitrosation of secondary amines is not a simple one. Tannins inhibit nitrosamine formation1, but in suitable conditions gallic acid catalyses the nitrosation of diethylamine, the rate being dependent on pH and gallic acid concentration2. Some phenolic constituents of smoked foods3 inhibit nitrosation of morpholine at pH 3.0. Phenolic compounds react with nitrite at a much faster rate than do secondary amines4, but chlorogenic acid and 4-methylcatechol catalyse5 the nitrosation of piperidine at gastric pH. We report here that nitrosophenols can catalyse N-nitrosamine formation.