Hexamethylphosphoramide

Hexamethylphosphoramide, often abbreviated HMPA, is a phosphoramide (an amide of phosphoric acid) with the formula [(CH3)2N]3PO. This colorless liquid is a useful reagent in organic synthesis.

Hexamethylphosphoramide
Names
Preferred IUPAC name
Hexamethylphosphoric triamide[1]
Other names
Hexamethylphosphoramide
Hexametapol
HMPA
Phosphoric tris(dimethylamide) (not recommended[1])
HMPT
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.010.595
KEGG
UNII
Properties
C6H18N3OP
Molar mass 179.20 g/mol
Appearance clear, colorless liquid[2]
Odor aromatic, mild, amine-like[2]
Density 1.03 g/cm3
Melting point 7.20 °C (44.96 °F; 280.35 K)
Boiling point 232.5 °C (450.5 °F; 505.6 K) CRC[3]
miscible[2]
Vapor pressure 0.03 mmHg (4.0 Pa) at 20 °C[2]
Hazards
Main hazards Suspected Carcinogen[2]
Safety data sheet Oxford MSDS
Flash point 104.4 °C (219.9 °F; 377.5 K)
NIOSH (US health exposure limits):
PEL (Permissible)
 none[2]
REL (Recommended)
 Ca[2]
IDLH (Immediate danger)
 Ca [N.D.][2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Structure and reactivity

HMPA is the oxide of the highly basic tertiary phosphine hexamethylphosphorous triamide (HMPT[note 1]), PO(NMe2)3. Like other phosphine oxides (such as triphenylphosphine oxide), the molecule has a tetrahedral core and a P=O bond that is highly polarized, with significant negative charge residing on the oxygen atom.

Compounds containing a nitrogen–phosphorus bond typically are degraded by hydrochloric acid to form a protonated amine and phosphate.

It dissolves alkali metals forming blue solutions which are stable for a few hours.[4] Solvated electrons are present in these blue solutions.[5]

Applications

HMPA is a specialty solvent for polymers, gases, and organometallic compounds. It improves the selectivity of lithiation reactions by breaking up the oligomers of lithium bases such as butyllithium. Because HMPA selectively solvates cations, it accelerates otherwise slow SN2 reactions by generating more bare anions. The basic nitrogen centers in HMPA coordinate strongly to Li+.[6]

HMPA is a ligand in the useful reagents based on molybdenum peroxide complexes, for example, MoO(O2)2(HMPA)(H2O) is used as an oxidant in organic synthesis.[7]

Alternative reagents

Dimethyl sulfoxide can often be used in place of HMPA as a cosolvent. Both are strong hydrogen bond acceptors, and their oxygen atoms bind metal cations. Other alternatives to HMPA include the N,N′-tetraalkylureas DMPU (dimethylpropyleneurea)[8][9] or DMI (1,3-dimethyl-2-imidazolidinone).[10] Tripyrrolidinophosphoric acid triamide (TPPA) has been reported to be a good substitute reagent for HMPA in reductions with samarium diiodide[11] and as a Lewis base additive to many reactions involving samarium ketyls.[12]

Toxicity

HMPA is only mildly toxic but has been shown to cause cancer in rats.[6] HMPA can be degraded by the action of hydrochloric acid.

Notes
  1. Confusingly, some sources (such as e-EROS) list HMPT as an abbreviation for O=P(NMe2)3 (hexamethylphosphoric triamide), as well as an abbreviation for PO(NMe2)3 (hexamethylphosphorous triamide).

References
  1. "Front Matter". Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. pp. P001–P004. doi:10.1039/9781849733069-FP001. ISBN 978-0-85404-182-4.
  2. NIOSH Pocket Guide to Chemical Hazards. "#0321". National Institute for Occupational Safety and Health (NIOSH).
  3. Haynes, William M. (2010). Handbook of Chemistry and Physics (91 ed.). Boca Raton, Florida, USA: CRC Press. p. 3-280. ISBN 978-1-43982077-3.
  4. Luehrs, Dean C.; Kohut, John P. (1974). "Hexamethylphosphoramide solvates of alkali metal salts". Journal of Inorganic and Nuclear Chemistry. 36 (7): 1459–1460. doi:10.1016/0022-1902(74)80605-6.
  5. Gremmo, Norberto; Randles, John E. B. (1974). "Solvated electrons in hexamethylphosphoramide. Part 1.—Conductivity of solutions of alkali metals". Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases. 70: 1480–1487. doi:10.1039/F19747001480.
  6. Dykstra, R. R. (2001). "Hexamethylphosphoric Triamide". Encyclopedia of Reagents for Organic Synthesis. New York, NY: John Wiley & Sons. doi:10.1002/047084289X.rh020. ISBN 978-0471936237.
  7. Dickman, Michael H.; Pope, Michael T. (1994). "Peroxo and Superoxo Complexes of Chromium, Molybdenum, and Tungsten". Chemical Reviews. 94 (3): 569–584. doi:10.1021/cr00027a002.
  8. Mukhopadhyay, T.; Seebach, D. (1982). "Substitution of HMPT by the Cyclic Urea DMPU as a Cosolvent for highly Reactive Nucleophiles and Bases". Helvetica Chimica Acta. 65 (1): 385–391. doi:10.1002/hlca.19820650141.
  9. Beck, A. K.; Seebach, D. (2001). "N,N′-Dimethylpropyleneurea". Encyclopedia of Reagents for Organic Synthesis. New York: John Wiley & Sons. doi:10.1002/047084289X.rd366. ISBN 978-0471936237.
  10. Lo, Chi-Chu; Chao, Pei-Min (1990). "Replacement of carcinogenic solvent HMPA by DMI in insect sex pheromone synthesis". Journal of Chemical Ecology. 16 (12): 3245–3253. doi:10.1007/BF00982095. PMID 24263426.
  11. McDonald, Chriss E.; Ramsey, Jeremy D.; Sampsell, David G.; Butler, Julie A.; Cecchini, Michael R. (2010). "Tripyrrolidinophosphoric Acid Triamide as an Activator in Samarium Diiodide Reductions". Organic Letters. 12 (22): 5178–5181. doi:10.1021/ol102040s. PMID 20979412.
  12. Berndt, Mathias; Hölemann, Alexandra; Niermann, André; Bentz, Christoph; Zimmer, Reinhold; Reissig, Hans-Ulrich (2012). "Replacement of HMPA in Samarium Diiodide Promoted Cyclizations and Reactions of Organolithium Compounds". European Journal of Organic Chemistry. 2012 (7): 1299–1302. doi:10.1002/ejoc.201101830. ISSN 1099-0690. Tripyrrolidinophosphoric acid triamide (TPPA) can replace carcinogenic HMPA as a Lewis basic additive in many reactions involving samarium ketyls. In most cases, yields and selectivities of cyclizations of (het)aryl, alkenyl, and alkynyl ketones are similar.
  • "Hexamethylphosphoramide CAS No. 680-31-9" (PDF). Report on Carcinogens (12th ed.). National Toxicology Program, Department of Health and Human Services. 2011.
  • "Hexamethyl phosphoramide". NIOSH Pocket Guide to Chemical Hazards. Centers for Disease Control and Prevention, Department of Health and Human Services. 2011.
  • Merck Index. 4761 (12th ed.).
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