[23328-69-0]  · C4H8ClNO  · N-Chloromorpholine  · (MW 121.57)

(useful reagent for selective and efficient chlorination of activated aromatics1)

Alternate Name: NCM.

Physical Data: bp 63-64 °C/36-38 mmHg.1

Solubility: sol diethyl ether, trifluoroacetic acid, carbon tetrachloride.

Preparative Methods: not commercially available; prepared from Morpholine and aqueous Sodium Hypochlorite at <10 °C, followed by ether extraction, concentration below 30 °C, and vacuum distillation.1,2

Analysis of Reagent Purity: can be determined iodometrically.3

Handling, Storage, and Precautions: lachrymatory liquid; begins to decompose at ambient temperature within hours, or on distillation at atmospheric pressure.4 Preferably used immediately after distillation; however, can be stored at -18 °C for several weeks with limited decomposition. Solid which forms on standing (morpholine hydrochloride) can be removed by filtration just before use.1 Store under inert atmosphere. This reagent should be handled in a fume hood.

Chlorination of Activated Aromatics.

Phenol, anisole, and related activated aromatic compounds are selectively chlorinated by N-chloromorpholine (NCM) in the para position in high yield, with formation of only small amounts of the corresponding ortho isomers. For example, 2-chloroanisole and NCM afford 2,4-dichloroanisole in 80% yield (eq 1). Less than 1% each of 2,6-dichloroanisole and 2,4,6-trichloroanisole are obtained under these conditions.1

Salicylic acid and NCM also give chlorination mainly para to the phenolic hydroxyl group (eq 2).5

These chlorinations are usually carried out in either trifluoroacetic acid or 80% aqueous sulfuric acid. In the latter solvent, highly activated substrates such as phenols can undergo ring sulfonation. Such side reactions can generally be minimized by keeping the reaction mixtures cold and employing short reaction times.1,5

Other structurally similar chlorinating agents, such as N-chloropiperidine (NCP), have also been used for selective para chlorination of activated aromatics. There appears to be no strong preference for use of NCM over NCP or related compounds, as overall yields and isomer ratios are generally excellent with each of these reagents.1 Mechanistic details of these transformations have been published.6

Unfortunately, NCM as well as other reagents in this family chlorinate less activated aromatics such as alkylbenzenes relatively unselectively, to afford mixtures of 2- and 4-substituted products.7 The isomer ratio can be affected by changing the acid strength of the solvent,7a or by use of added silica gel;3 however, only limited specificity for one isomer can be obtained in this fashion.

Chlorodealkylation of Alkyl Phenols.

t-Butyl substituted phenols react with NCM to substitute chlorine for the t-butyl group (eq 3).5

Other Reactions.

NCM can be used to prepare morpholino-substituted sulfenamides8 and selenamides9 upon reaction with alkyl sulfides and selenides, respectively. Such amides have been used as vulcanization accelerators in the rubber industry.

1. Smith, J. R. L.; McKeer, L. C.; Taylor, J. M. OSC 1993, 8, 167.
2. Smith, J. R. L.; McKeer, L. C.; Taylor, J. M. JCS(P2) 1987, 1533.
3. Smith, K.; Butters, M. TL 1988, 29, 1319.
4. Henry, R. A.; Dehn, W. M. JACS 1950, 72, 2280.
5. Smith, J. R. L.; McKeer, L. C.; Taylor, J. M. JCS(P2) 1988, 385.
6. (a) Smith, J. R. L.; McKeer, L. C.; Taylor, J. M. JCS(P2) 1989, 1529 (b) Higuchi, T.; Hussain, A.; Pitman, I. H. JCS(B) 1969, 626.
7. (a) Smith, J. R. L.; McKeer, L. C.; Taylor, J. M. JCS(P2) 1989, 1537. (b) Minisci, F.; Vismara, E.; Fontana, F.; Platone, E.; Faraci, G. JCS(P2) 1989, 123.
8. Barton, D. H. R.; Hesse, R. H.; O'Sullivan, A. C.; Pechet, M. M. JOC 1991, 56, 6702.
9. (a) Hosay, Th.; Christiaens, L.; Anthoine, G.; Moniotte, Ph. TL 1990, 31, 873. (b) Derkach, N. Ya.; Lyapina, T. V. ZOR 1981, 17, 529.

Howard Sard

Organix, Woburn, MA, USA

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