More than ever, the work from Ashworth et al. is so relevant.
Conditions Proposed as standard for nitrosation exploration
Condition 1
Charge the potentially vulnerable amine as a free base or salt and acetic acid to a reaction vessel. The volume of acetic acid should be around 30% of the total final reaction volume. To the reaction vessel, charge an aqueous solution of sodium nitrite (1.5 equiv). The target reaction concentration is 0.1 M with respect to the input amine. The reaction mixture should be held at a temperature of 20–25 °C with a minimized and static headspace to avoid NOx depletion and sampled after 1, 4, and 24 h for analysis. The reaction mixture may be a slurry; care should be taken to ensure that the reaction mixture is sufficiently agitated. To avoid side reactions, no additional cosolvents should be used. The large excess of acetic acid used will ensure no significant impact on reaction pH from the charge of the amine, amine salt, or nitrite.
Example: N-Methylaniline (107 mg, 1 mmol, 1 equiv) was weighed into a 20 mL vial equipped with a stir bar. Acetic acid (3 mL) was added to the reaction vial. An aqueous solution of sodium nitrite (103 mg, 1.5 mmol, 1.5 equiv in 7 mL of water) was added to the reaction vessel, resulting in a reaction concentration of 0.1 M. The reaction mixture was held under agitation at 20–25 °C with a static headspace and was sampled after 1, 4, and 24 h for analysis.
Condition 2
Charge the potentially vulnerable amine as a free base or salt to a reaction vessel. Add water followed by dilute aqueous hydrochloric acid to obtain a pH between 3 and 4. If the substrate is the salt of a strong acid, addition of hydrochloric acid may not be required to obtain the desired pH. If the addition of hydrochloric acid is not required, charge 1 equiv of sodium chloride to the reaction vessel instead to ensure presence of chloride ions. To the reaction vessel, charge an aqueous solution of sodium nitrite (1.5 equiv) and adjust the pH to 3–4 with dilute HCl if required. The target reaction concentration is 0.1 M with respect to the input amine. The reaction mixture should be held at a temperature of 20–25 °C with a minimized and static headspace to avoid NOx depletion and sampled after 1, 4, and 24 h for analysis. At each sampling point, the pH should be checked and adjusted with dilute HCl if necessary to maintain the desired range of pH 3–4. The reaction mixture may be a slurry; care should be taken to ensure that the reaction mixture is sufficiently agitated. To avoid side reactions, no additional cosolvents should be used.
Example: N-Methylaniline (107 mg, 1 mmol, 1 equiv) was weighed into a 20 mL vial equipped with a stir bar. Water (5 mL) was added, and the pH was checked. In the case of pH > 4, the solution pH was carefully adjusted to pH 3–4 using 1 M aqueous HCl. An aqueous solution of NaNO2 (103 mg, 1.5 mmol, 1.5 equiv in 4 mL of water) was then added. The target reaction concentration was 0.1 M. The reaction mixture was held under agitation at 20–25 °C with a static headspace and was sampled after 1, 4, and 24 h for analysis.
Condition 3
Charge the potentially vulnerable amine as a free base to the reaction vessel and add an organic aprotic solvent that solubilizes the amine (for example, acetonitrile, THF, or DCM). To the reaction vessel add tert-butyl nitrite (1.5 equiv). The target reaction concentration is 0.1 M. The reaction mixture should be held at a temperature of 20–25 °C with a minimized and static headspace to avoid NOx depletion and sampled after 1, 4, and 24 h for analysis.
These reactions can usefully be performed with deuterated solvent in an NMR tube with a Young’s tap closure to enable real-time monitoring of the reaction by NMR if desired. Use of the amine free base allows the exploration of neutral nitrosation conditions in organic media.
Example: N-Methylaniline (107 mg, 1 mmol, 1 equiv) was weighed into a 20 mL vial equipped with a stir bar. DCM (10 mL) was added. tert-Butyl nitrite (155 mg, 1.5 mmol, 1.5 equiv) was charged. The reaction mixture was held under agitation at 20–25 °C with a static headspace and was sampled after 1, 4, and 24 h for analysis.