Hexamethylphosphoramide

HMPA is the oxide of tris(dimethylamino)phosphine, P(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 metal salts{{cite journal |doi=10.1016/0022-1902(74)80605-6 |title=Hexamethylphosphoramide solvates of alkali metal salts |journal=Journal of Inorganic and Nuclear Chemistry |volume=36 |issue=7 |pages=1459–1460 |year=1974 |last1=Luehrs |first1=Dean C. |last2=Kohut |first2=John P. }} and alkali metals, forming blue solutions which are stable for a few hours. Solvated electrons are present in these blue solutions.{{cite journal |doi=10.1039/F19747001480 |title=Solvated electrons in hexamethylphosphoramide. Part 1.—Conductivity of solutions of alkali metals |journal=Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases |volume=70 |pages=1480–1487 |year=1974 |last1=Gremmo |first1=Norberto |last2=Randles |first2=John E. B. }}

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 S_N2 reactions by generating more bare anions. The basic nitrogen centers in HMPA coordinate strongly to Li⁺.{{cite encyclopedia | last = Dykstra | first = R. R. | title = Hexamethylphosphoric Triamide | encyclopedia = Encyclopedia of Reagents for Organic Synthesis | year = 2001 | publisher = John Wiley & Sons | location = New York, NY | doi = 10.1002/047084289X.rh020| entry = Hexamethylphosphoric Triamide | isbn = 978-0471936237 }}

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.{{cite journal | last1 = Dickman | first1 = Michael H. | last2 = Pope | first2 = Michael T. | year = 1994 | title = Peroxo and Superoxo Complexes of Chromium, Molybdenum, and Tungsten | journal = Chemical Reviews | volume = 94 | issue = 3| pages = 569–584 | doi = 10.1021/cr00027a002}}

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){{cite journal | title = Substitution of HMPT by the Cyclic Urea DMPU as a Cosolvent for highly Reactive Nucleophiles and Bases | last1 = Mukhopadhyay |first1=T. | last2 = Seebach |first2=D. | author-link2 = Dieter Seebach | journal = Helvetica Chimica Acta | volume = 65 | issue = 1 | pages = 385–391 | year = 1982 | doi = 10.1002/hlca.19820650141 | title-link = DMPU }}{{cite encyclopedia |author1=Beck, A. K. |author2=Seebach, D. |title=N,N′-Dimethylpropyleneurea | entry = N,N′-Dimethylpropyleneurea | encyclopedia = Encyclopedia of Reagents for Organic Synthesis | year = 2001 | publisher = John Wiley & Sons | location = New York | doi = 10.1002/047084289X.rd366 |isbn=978-0471936237 }} or DMI (1,3-dimethyl-2-imidazolidinone).{{cite journal |doi=10.1007/BF00982095 |pmid=24263426 |title=Replacement of carcinogenic solvent HMPA by DMI in insect sex pheromone synthesis |journal=Journal of Chemical Ecology |volume=16 |issue=12 |pages=3245–3253 |year=1990 |last1=Lo |first1=Chi-Chu |last2=Chao |first2=Pei-Min |s2cid=9859086 }} Tripyrrolidinophosphoric acid triamide (TPPA) has been reported to be a good substitute reagent for HMPA in reductions with samarium diiodide{{cite journal|last1=McDonald|first1=Chriss E.|last2=Ramsey|first2=Jeremy D.|last3=Sampsell|first3=David G.|last4=Butler|first4=Julie A.|last5=Cecchini|first5=Michael R.|title=Tripyrrolidinophosphoric Acid Triamide as an Activator in Samarium Diiodide Reductions|journal=Organic Letters|volume=12|pages=5178–5181|year=2010|doi=10.1021/ol102040s|issue=22|pmid=20979412}} and as a Lewis base additive to many reactions involving samarium ketyls.{{Cite journal |last1=Berndt |first1=Mathias |last2=Hölemann |first2=Alexandra |last3=Niermann |first3=André |last4=Bentz |first4=Christoph |last5=Zimmer |first5=Reinhold |last6=Reissig |first6=Hans-Ulrich |date=2012 |title=Replacement of HMPA in Samarium Diiodide Promoted Cyclizations and Reactions of Organolithium Compounds |journal=European Journal of Organic Chemistry |language=en |volume=2012 |issue=7 |pages=1299–1302 |doi=10.1002/ejoc.201101830 |issn=1099-0690|quote=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.}}

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

{{Reflist|30em}}

• {{ cite web | url = https://ntp.niehs.nih.gov/ntp/roc/content/profiles/hexamethylphosphoramide.pdf | title = Hexamethylphosphoramide CAS No. 680-31-9 | work = Report on Carcinogens |edition=12th | year = 2011 | publisher = National Toxicology Program, Department of Health and Human Services }}
• {{ cite web | url = https://www.cdc.gov/niosh/npg/npgd0321.html | title = Hexamethyl phosphoramide | work = NIOSH Pocket Guide to Chemical Hazards | year = 2011 | publisher = Centers for Disease Control and Prevention, Department of Health and Human Services }}
• {{cite book|title=Merck Index|edition=12th|volume=4761}}

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Category:Phosphoramides

Category:Solvents

Category:IARC Group 2B carcinogens