1-Methyl-2-pyrrolidinone1

[872-50-4]  · C5H9NO  · 1-Methyl-2-pyrrolidinone  · (MW 99.15)

(special solvent;1 source of enolates2)

Alternate Names: NMP; N-methylpyrrolidone.

Physical Data: mp -24.4 °C; bp 202 °C; d 1.030 g cm-3.

Solubility: completely misc H2O and virtually all organic solvents.

Form Supplied in: colorless liquid. Drying: dry over anhydrous K2CO3 and anhydrous cerium(IV) sulfate and purify by vacuum distillation through a 50 cm Vigreux column; or distill from CaH2 and store over 4Å molecular sieves.

Handling, Storage, and Precautions: can be handled safely since it has a high flash point (95 °C), low vapor hazard, high boiling and low freezing points, and good chemical and thermal stability; hydrolyzed by 4% NaOH to the extent of 50-70% in 8 h. The lactam ring is cleaved when exposed to conc HCl for an extended period of time.

Solvent.

NMP is an effective solvent for both inorganic and organic compounds. H-bond basicity in tertiary amides is decreased more by bulky substituents on carbon than by bulky substituents on nitrogen.3 Thus, the pKHB values for DMF, NMP, and N-methyl-2-piperidinone are 2.10, 2.38, and 2.57, respectively. Some measure of the nucleophilicity of NMP is provided by the equilibrium constant for salt formation with trimethylsilyl triflate.4 The Krel of salt formation decreases in the order: 4-dimethylaminopyridine (32 800) > N-methyl-2-pyridone (182) > NMP (1.0) > DMF (0.81) > pyridine (0.10). NMP has advantages over both Dimethyl Sulfoxide and N,N-Dimethylformamide for nucleophilic displacement reactions because of its greater stability, and over Hexamethylphosphoric Triamide because of the lack of adverse physiological properties. NMP has superior properties for several nucleophilic disp lacement reactions:5 2- and 4-halo-1,8-naphthalic anhydrides and imides undergo very smooth aromatic substitution with n-butylamine, Copper(I) Cyanide, and Sodium Methoxide. The alkylation of lithioalkynes also works exceptionally well in NMP.5 Other nucleophilic substitutions have been explored: hydrolysis of halodaunomycinones to adriamycinones,6 hydrolysis of primary alkyl iodides and bromides to alcohols,7 and substitution of alkyl iodides and bromides with inorganic Li salts.1b

Alkylation of the carbanion from ethyl 6-methylsalicylate O-methyl ether8 has been performed in NMP. The intramolecular nucleophilic displacement of halogen by the carbonyl oxygen of an acylsilane and subsequent cyclization to 2-silyldihydropyrans (eq 1) is accelerated in NMP.9

A simple, safe, and inexpensive synthesis of Cyanotrimethylsilane has been achieved from Chlorotrimethylsilane and metal cyanides in NMP (DMF and DMSO are not inert).10 Some earlier experiments with TMSCN in situ failed. With NMP the product is distilled directly from the pot. The use of NMP raises the yield of the alkynic oxy-Cope rearrangement.11 The catalytic conversion of Methyl Formate to Acetic Acid (eq 2) works best in NMP as solvent, with Palladium(II) Acetate as catalyst (<1%), and Lithium Iodide as promoter.12

NMP is also an effective solvent for the decarbonylation of aldehydes. At 110-130 °C in the presence of Chlorotris(triphenylphosphine)rhodium(I), simple aldoses are converted to the lower alditols. The decarbonylation of sugars has only recently been accomplished, probably for the lack of a compatible solvent.13 The carbonylation of alkenes (1-decene) to aldehydes by a copper-based catalyst system gives the best yields with CuCl/PPh3/NMP.14 There are several advantages to using NMP as cosolvent for CuII catalyzed alkylation of organomanganese chloride reagents. The reactions are easier to perform, no excess of organometallics is required, and higher yields and better selectivity are observed (eq 3).15

The reducing power of telluride anion is enhanced in hot NMP.16 Benzaldehydes and ketones are reduced to the corresponding alcohols (halogens in the molecule are displaced with telluride). Few byproducts are formed, since Cannizzaro-type disproportionation does not occur. Aromatic nitriles are usually inert to Na2Te, but in NMP they form 7-deaza-9H-purines (eq 4). Sodium Telluride in NMP is formed at 100-110 °C as a deep purple solution, whereas in DMF it forms a yellow suspension at 140 °C.

NMP as a Reagent.

Amidines formed from NMP exist as amidine-enediamine tautomers.17 C-Michael addition leads to functionalized pyrrolidines (eq 5). The stereochemistry of Michael additions of amide or thioamide enolates to a,b-unsaturated ketones has been studied.2 NMP is a model for an (E) lithium enolate (eq 6). Preferential 1,4-addition is observed. Oxo lactams give higher proportions of the anti-diastereomers, whereas thiolactams (softer enolates)18 give mainly the syn-diastereomers.2b The preference for syn-isomers is better seen with K and Na enolates than with the Li analogs.

Enamine formation from NMP (unactivated lactam) with various Li reagents has been achieved.19 The enolate of NMP reacts with many electrophiles to introduce functions into the 3-position of NMP. Thus nitroalkenyl,20a bromo,20b chloro,20c alkyl, allyl,20a,d nitro,20c and phosphonic acid20f derivatives can be formed.

Related Reagents.

N,N-Dimethylpropyleneurea; Dimethyl Sulfoxide; Hexamethylphosphoric Triamide.


1. (a) Riddick, J. A.; Bunger, W. B.; Sakano, T. K. Organic Solvents. Physical Properties and Methods of Purification, 4th ed.; Wiley: New York, 1986. (b) Virtanen, P. O. I. Suom. Kemistil. 1966, 39, 257.
2. (a) Heathcock, C. H.; Henderson, M. A., Oare, D. A., Sanner, M. A. JOC 1985, 50, 3019. (b) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock, C. H. JOC 1990, 55, 132.
3. Le Questel, J.-Y.; Laurence, C.; Lachkar, A.; Herbert, M.; Berthelot, M. JCS(P2) 1992, 2091.
4. Bassindale, A. R.; Stout, T. TL 1985, 26, 3403.
5. Tyman, J.; Ghorbanian, S.; Muir, M.; Tychopoulous, V.; Bruce, I.; Fischer, I. SC 1989, 19, 179.
6. Terajima, A.; Kimura, Y.; Suzuki, M.; Abe, R.; Matsumoto, M. Jpn. Patent 6 107 289, 1986 (CA 1986, 105, 134 297x).
7. Hutchins, R. O.; Taffer, I. M. JOC 1983, 48, 1360.
8. Tyman, J. H. P.; Visani, N. In Topics in Lipid Research; Klein, R.; Schmitz, B., Eds.; Royal Society of Chemistry: London, 1986; p 109.
9. Tsai, Y.-M.; Nieh, H.-C.; Cherng, C.-D. JOC 1992, 57, 7010.
10. (a) Hünig, S.; Wehner, G. S 1979, 522. (b) Rasmussen, J. K.; Heilmann, S. M. S 1979, 523.
11. (a) Onishi, T.; Fujita, Y.; Nishida, T. CC 1978, 651. (b) Fujita, Y.; Onishi, T.; Nishida, T. S 1978, 934.
12. Jenner, G. TL 1990, 31, 3887.
13. Andrews, M. A.; Gould, G. L.; Klaeren, S. A. JOC 1989, 54, 5257.
14. Hagen, J.; Tschirner, E. G.; Fink, G.; Lorenz, R. CZ 1985, 109, 3.
15. Cahiez, G.; Marquais, S. SL 1993, 45.
16. Suzuki, H.; Nakamura, T. JOC 1993, 58, 241.
17. Pfau, M.; Chiriancescu, M.; Revial, G. TL 1993, 34, 327.
18. Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O. OS 1984, 62, 158.
19. (a) Ban, Y.; Kimura, M.; Oishi, T. CPB 1976, 24, 1490. (b) Yamaguchi, M.; Hirao, I. JOC 1985, 50, 1975. (c) Pommelet, J.-C.; Dhimane, H.; Chuche, J.; Celerier, J.-P.; Haddad, M.; Lhommet, G. JOC 1988, 53, 5680.
20. (a) Node, M.; Itoh, A.; Nishide, K.; Abe, H.; Kawabata, T.; Masaki, Y.; Fuji, K. S 1992, 1119. (b) Caristi, G.; Ferlazzo, A.; Gattuso, M. G 1984, 114, 83. (c) Lambert, C.; Caillaux, B.; Viehe, H. G. T 1985, 41, 3331. (d) Cuvigny, T.; Hullot, P.; Larcheveque, M.; Normant, H. CR(C) 1974, 278, 1105. (e) Feur, H.; Panda, C. S.; Hon, L.; Bevinakatti, H. S. S 1983, 187. (f) Tay, M. K.; About-Jaudet, E.; Collignon, N.; Savignac, P. T 1989, 45, 4415.

Peteris Trapencieris

Latvian Institute of Organic Synthesis, Riga, Latvia



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.