Org. Synth. 2005, 81, 254
DOI: 10.15227/orgsyn.081.0254
PREPARATION OF PIVALOYL HYDRAZIDE IN WATER
[Propanoic acid, 2,2-dimethyl-, hydrazide]
Submitted by Bryan Li,
1, Raymond J. Bemish, David R. Bill, Steven Brenek, Richard A. Buzon, Charles K-F Chiu, and Lisa Newell.
Checked by Claire Coleman and Peter A. Wipf.
1. Procedure
Pivaloyl hydrazide. A 1-L, three-necked, round-bottomed flask equipped with a Teflon-coated thermocouple and mechanical stirrer is charged with 400 mL of water and sodium hydroxide (12.87 g, 322 mmol), and the resulting mixture is stirred until all of the solids dissolve (Note 1). Hydrazine (35% aqueous solution, 36.83 g, 400 mmol) is then added in one portion. The mixture is cooled in an ice-water/acetone bath to an internal temperature of −5 to 0°C, and trimethylacetyl chloride (38.6 mL, 320 mmol) is added dropwise (Note 2) over a period of 40-60 min while maintaining the reaction temperature between −5 and 0°C (Note 3). The reaction mixture is then transferred to a 1-L, pear-shaped flask and concentrated to a volume of ca. 100 mL by rotary evaporation (at ca. 100 mm) (Notes 4, 5) and the resulting suspension is filtered (Note 6). The filtrate is further concentrated to a volume of ca. 40 mL (Note 7) and 100 mL of toluene is then added. The resulting solution is transferred to a three-necked, round-bottomed flask equipped with a Dean-Stark water separator, thermometer, and rubber septum. Distillation is continued at atmospheric pressure until a constant boiling point is reached (Note 8) and then the pot volume is further reduced to ca. 40 mL. The resulting heterogenous mixture is filtered (Note 9) and the filtrate is concentrated by rotary evaporation under reduced pressure to provide the desired product as a colorless oil, which on standing solidifies to a white semi-solid. This material is recrystallized from 100 mL of isopropyl ether to afford 18.6-20.4 g (50-55%) of pivaloyl hydrazide (Notes 10, 11).
2. Notes
1.
All
reagents were purchased from Aldrich Chemical Company (except for
trimethylacetyl chloride, which the checkers obtained from Acros) and were used without further purification. The checkers used a low temperature alcohol
thermometer in place of a
Teflon-coated themocouple. The third neck of the flask was left open to the atmosphere.
2.
A
syringe pump was used for the addition of acid chloride in order to achieve a steady flow rate. The tip of the
syringe needle (gauge 20) was submerged in the reaction mixture. Dropwise addition of
trimethylacetyl chloride at 0–5°C resulted in the immediate formation of a precipitate.
3.
The reaction was complete at the end of the
pivaloyl chloride addition. On 5-L or larger scale, the reaction was conducted at temperatures of 10–15°C without loss of selectivity.
4.
A small amount of
hydrazine hydrate was present in the reaction mixture at this point, but a safety evaluation indicated the final reaction mixture had a very low thermal potential (ΔH = 15.3 J/g). This poses a minimum thermal hazard for vacuum distillation.
5.
The submitters concentrated the reaction mixture by vacuum distillation (100 mm, bath temperature 70°C, vapor temperature 51°C). The weight after concentration was ca. 120 g. The checkers used rotary evaporation with a bath temperature of 65 to 70°C without any problems, and employed an explosion shield as a safety precaution.
6.
The bis-acylation byproduct
(Me3CCONHNHCOCMe3) was removed by filtration; 20 mL of water was used for washing the filter cake.
7.
The submitters removed solvent by vacuum distillation (100 mm, bath temperature 70°C, vapor temperature 51°C).
8.
Azeotropic removal of water was complete when the vapor temperature reached 111°C.
9.
Sodium chloride was removed by filtration.
10.
The submitters obtained the product in
72% yield without recrystallization and determined the product to be >97% pure by HPLC (by area; conditions: 250 mm Kromasil C4 column using acetonitrile (A)/water (B) and 0.1% TFA in water (C), 0:90:10 A:B:C ramp to 90:0:10 A:B:C over 15 min and hold for 5 min. Flow rate 1 mL/min and detection wavelength 210 nm. The checkers found the purity prior to recrystallization to be typically 85-90% with the impurity determined to be the bis-acylation product by LC-MS. The checkers employed C8 microsorb-MW 100 (250 mm) and Alltech C18 (100 mm) columns using acetonitrile (A)/water (B) and 0.1% TFA in water (C), 0:90:10 A:B:C ramp to 90:0:10 A:B:C over 15 min and hold for 5 min. Flow rate 1 mL/min and detection wavelength 210 nm.
11.
The product exhibits the following physical properties:
mp 67.1-69.2°C; IR (NaCl) cm
−1 3471, 3327, 2968, 1660;
1H NMR
pdf (CDCl
3, 400 MHz): δ 1.19 (s, 9H), 4.40-4.85 (br, 3 H);
13C NMR (CDCl
3, 75 MHz): δ 27.4, 38.1, 179.3; MS (m/z): 117 ([M + 1]
+). Anal. Calcd for C
5H
12N
2O: C, 51.70; H, 10.41; N, 24.12. Found C, 51.62; H, 10.78; N, 24.22.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Hydrazides (RCONHNH
2) are highly useful starting materials and intermediates in the synthesis of heterocyclic molecules.
2 They can be synthesized by hydrazinolysis of amides, esters and thioesters.
3 The reaction of hydrazine with acyl chlorides or anhydrides is also well known,
4 but it is complicated by the formation of 1,2-diacylhydrazines, and often requires the use of anhydrous
hydrazine which presents a high thermal hazard. Diacylation products predominate when
hydrazine reacts with low molecular weight aliphatic acyl chlorides, which makes the reaction impractical for preparatory purposes.
5Recently we needed to prepare large amounts of
pivaloyl hydrazide (
1). A literature survey indicated several approaches: (1) heating
pivalic acid with
hydrazine hydrate with a Lewis acid catalyst such as activated
alumina6 or
titanium oxide;
7 (2) heating
hydrazine hydrate at high temperature (140°C) with
ethyl pivalate;
8 (3) condensing
phthaloyl hydrazine with
pivaloyl chloride, followed by deprotection of the phthaloyl group;
9 and (4) reaction of
ethyl thiopivalate with
hydrazine hydrate. Reaction safety evaluations revealed that hydrazine monohydrate has an onset temperature of
ca. 125°C in a Differential Scanning Calorimetry (DSC) experiment, and possesses a very high thermal potential (ΔH = 2500 J/g),
10,11 which prompted us to develop a method for the synthesis of
1 that did not require heating. After some experimentation we determined that the reaction of
pivaloyl chloride with
hydrazine proceeds most efficiently in water to give a 4:1 ratio
12 of
1 to Me
3CCONHNHCOCMe
3 (
2). The use of organic solvents (
MeOH,
THF,
2-propanol) with water
13 invariably led to formation of biphasic mixtures and predominant formation of
2.
14 Reaction workup is also simplified using water as solvent. Upon partial concentration the bis-acylhydrazide by-product
2 precipitated out of the reaction mixture and is conveniently removed by filtration. Removal of the remainder of the water by displacement with
toluene leads to precipitation of
NaCl, which is also easily removed by filtration. The filtrate is then further concentrated to provide
1 in >97% purity, typically in
55-75% yield. This procedure has been employed to prepare 10 Kg batches of
1 with no difficulty.
The protocol is effective in preparation of hydrazides of 5 carbons or less.
Cyclopropanecarboxylic acid hydrazide15 and
isobutyric acid hydrazide16 were prepared from their corresponding acid chlorides in
64% and
71% yields, respectively. However, when this method was applied to cyclohexanecarboxylic acid chloride, the bis-acylhydrazide was the predominant product, and the mono-acylhydrazide
17 was isolated in 25% yield.
18
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Hydrazine; (10217-52-4)
Pivaloyl chloride:
Propanoyl chloride, 2,2-dimethyl-; (3282-30-2)
Pivaloyl hydrazide:
Propanoic acid, 2,2-dimethyl-, hydrazide; (42826-42-6)
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