Sciencemadness Discussion Board

Hofmann rearrangement of 3,4,5-trimethoxybenzamide using household bleach

DrDevice - 15-4-2016 at 22:08

To support a series of experiments to obtain various phenylhydrazines, the following experiment was undertaken using a benzamide as a starting material. This procedure is a tidied up version of the one in the Organic section of ScienceMadness.

Benzamide hofmann.gif - 6kB

Domestic bleach solution titred to 0.97M was used. The bleach was several months old, and from an open bottle, by the time the experiment took place.

Dissolve 6.2g (0.16 mol) NaOH in 88ml of 0.97M (0.085 mol) sodium hypochlorite solution and chill in fridge to 4C.

Add approx 40g ice.

With magnetic stirring, add 16.33g (77.3 mmol) of 3,4,5-trimethoxybenzamide all at once. Continue stirring for a further 10 minutes.

Increase the temperature to 70C over an interval of about an hour, and then add a solution of 9.2g of NaOH in 20ml water. Continue heating and stirring at 70C for a further hour. The solution becomes a dark red-brown colour.

After the initial temperature increase, a precipitate begins to form. On removal from heat, a further mass of crystals form.

The loose fluffy product is filtered and washed with ice cold water. The product is slightly soluble in water, so some loss occurs at this time. The filtered solid is air dried.

Measured melting point of product = 110C cf lit. 110 - 113.

Yield 3,4,5-trimethoxyaniline was 8.5g = 60%.


"The Hofmann Rearrangement Using Household Bleach : Synthesis of 3-Nitroaniline"(Monk, Mohan 1999),

Nicodem - 24-4-2016 at 01:55

Thanks for the contribution. There is not much to add. I'm surprised you got such a close mp without a recrystallization. Was the product brown? Did you synthesize the starting material yourself?

Link to discussion thread on this reaction:

I could find some references for the Hofmann rearrangement of 3,4,5-trimethoxybenzamide:

With NaOCl:
3,4,5-Trimethoxyaniline (3) To 600 ml of 12% commercial sodium hypochlorite solution and 600 ml 2 M NaOH, compound 2 (160.0 g, 0.75 mol)was added in portions over 30 minutes. The reactionmixture was vigorously stirred below 25 °C until TLC showed that compound 2 had disappeared; the reaction mixture was then heated to 100 °C under stirring. After the reaction was complete, it was cooled and the solid was collected and saved. The filtrate was extracted with CH2Cl2 (2 × 2000 ml) and the extracts were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a solid. This solid was combined the solid above and recrystallized from water to give compound 3 White crystals (109.7 g, 80% yield). mp. 111-113 C, lit.13110-110.5 C. 1HNMR: δ5.95(s, 2H), 3.82(s, 6H), 3.77(s, 3H). MS (m/e): 183(M+).

Cited from: An Alternate Preparation of 3,4,5-Trimethoxyphenol
Qi-Xue Qin , Jian Yang , Duo-Zhi Chen , Bo Yang , Ji Zhang
Organic Preparations and Procedures International, 2013, 45, 321-324.
DOI: 10.1080/00304948.2013.798570

From DOI: 10.3969/j.issn.0253-2417.2013.04.018 (English abstract):
The optimal reaction conditions of (3,4,5-trimethoxybenzamide) was as follows: n(ammonia):n(3,4,5-trimethoxybenzoyl chloride)=4:1, reaction temperature-5-0℃, reaction time 30 min. The optimal reaction conditions of (3,4,5-trimethoxyaniline) was as follows: n(NaOH):n(3,4,5-trimethoxybenzamide)=9:1, n(Br2):n(3,4,5-trimethoxybenzamide)=1.15:1, rearrangement reaction temperature 40℃, rearrangement reaction time 20 min, decarboxylation temperature 85℃, decarboxylation time 1 h, deionized water as the solvent. Yield of obtained product was 66.8%, m.p. 112.5-113.5℃, purity of obtained product was 99.0%.

Bioorganic & Medicinal Chemistry, 2014, 22, 738-755 describes a related synthesis from 3,4,5-trimethoxybenzoic acid using the related Curtius rearrangement. A Lossen rearrangement is described in Advanced Synthesis & Catalysis, 2013, 355, 81-86.

A very interesting strategy is used in WO2012092880. Here they nitrated 3,4,5-trimethoxybenzoic acid with HNO3 to obtain an ipso substituted product 3,4,5-trimethoxynitrobenzene. This is then reduced to 3,4,5-trimethoxyaniline. Quite surprising that the nitration would give nitrodecarboxylation with useful selectivity:
1,2,3-trimethoxy-5-nitrobenzene To a solution of nitric acid (20.0 mL) and acetic acid (40.0 mL) under 10 °C was added 3,4,5-trimethoxybenzoic acid (10.0 g, 47.0 mmol) in portions. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured into ice-water. The resulting precipitate was collected by filtration and washed with water, which was then recrystallized from ethanol to afford the product 1,2,3-trimethoxy-5-nitrobenzene. Yield 6.64 g, 66.1 %. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51 (s, 2H), 3.87 (s, 6H), 3.77 (s, 3H).