Hexamethylphosphoric Triamide

[680-31-9]  · C6H18N3OP  · Hexamethylphosphoric Triamide  · (MW 179.24)

(high Lewis acid basicity; dipolar aprotic solvent with superb ability to form cation-ligand complexes; can enhance the rates of a wide variety of main group organometallic reactions and influence regio- or stereochemistry; additive in transition metal chemistry; UV inhibitor in poly(vinyl chloride))

Alternate Names: HMPA; hexamethylphosphoramide; hexametapol; hempa; HMPT.

Physical Data: mp 7.2 °C; bp 230-232 °C/740 mmHg; d 1.025 g cm-3; mild amine odor.

Solubility: sol water, polar and nonpolar solvents.

Form Supplied in: water-white liquid. Drying: distilled from CaH2 or BaO1 at reduced pressure and stored under N2 over molecular sieves.

Handling, Storage, and Precautions: has low to moderate acute toxicity in mammals.2a Inhalation exposure to HMPA has been shown to induce nasal tumors in rats,2b and has been classified under Industrial Substances Suspect of Carcinogenic Potential for Man.2c Adequate precautions must be taken to avoid all forms of exposure to HMPA.

Introduction.

Hexamethylphosphoric triamide has been used extensively as an additive in organolithium chemistry.3 It is among the strongest of electron pair donors and is superior to protic solvents in that it solvates the cation much better than the anion.4 This coordinating ability gives HMPA its unusual chemical properties.5,6 For instance, HMPA dramatically enhances the rates of a wide variety of organolithium reactions, as well as significantly influencing regio- or stereochemistry. The reactivity or selectivity effects of HMPA are usually rationalized in terms of changes in either aggregation state or ion pair structure.7 The breaking up of aggregates to form reactive monomers or solvent-separated ion pairs is often invoked.

Organolithium Reagent Solution Structure.

The rate of metalation reactions with Lithium Diisopropylamide as base are significantly increased through the use of HMPA.8 Treatment of LDA dimer with HMPA causes sequential solvation of the lithium cation, but no significant deaggregation;8,9 nor does HMPA promote the break up of tetrameric unhindered phenoxides10,11 or tetrameric MeLi.12 A chiral bidentate lithium amide,13 however, was converted from a dimer to a monomer by HMPA, with an increase in reactivity and enantioselectivity in deprotonation (eq 1). HMPA also converts Phenyllithium dimer into monomer.12,14 Other aggregated lithium reagents12 in THF (MeSLi, LiCl) or ether (Ph2PLi, PhSeLi) are first deaggregated to monomers, and then solvent-separated ion pair species are formed.12,15 HMPA may exert its reactivity effects by a combination of one or more of the following:

  • 1)lowering the degree of aggregation16,17 or forming separated ions,18
  • 2)increasing reactivity through cation coordination,17
  • 3)activating the aggregate through insertion into the aggregate site normally occupied by the anionic fragment,5,19
  • 4)promoting triple ion (ate complex) formation.16a,20

    HMPA can have large effects on equilibria. Phenyllithium reacts with Diphenylmercury, Diphenyl Ditelluride, and iodobenzene in THF to form ate complexes. In THF/HMPA the ate complex formation constants are dramatically higher than in THF.14,21

    Enolate Formation.

    The formation of lithium enolates is one instance where HMPA is sometimes needed.22 The difficult generation of dimethyl tartrate acetonide enolate23 and subsequent benzylation (eq 2), as well as the double deprotonation of methyl 3-nitropropanoate,24 become possible (eq 3) with the addition of HMPA (or N,N-Dimethylpropyleneurea).25

    Enolate Reactivity.

    Not only is HMPA necessary to the generation of enolates, it is often needed in the electrophilic trapping of enolates (eqs 4-6).26,31 Studies of the electrophilic trapping of enolates have demonstrated that substantial increases in reaction rates can be achieved through the use of a polar aprotic solvent like HMPA.4

    The desired [2,3]-sigmatropic rearrangement of a bis-sulfur cyano-stabilized lithium salt did not proceed (eq 7) without the addition of 25% HMPA.27 Sometimes higher O/C-alkylation ratios are obtained in THF-HMPA.28

    Enolate Stereochemistry.

    Stereochemical control of an ester enolate Claisen rearrangement was accomplished through stereoselective enolate formation.29 The enolization of 3-pentanone with LDA afforded predominantly the (E)-enolate in THF and the (Z)-enolate in THF-HMPA, as shown by chlorotrialkylsilane trapping experiments (eq 8). Similar stereoselectivity (Z:E = 94:6) was obtained with the dipolar aprotic cosolvent DMPU.30

    In addition to altering the (E/Z) isomer ratio of enolates,17,32 HMPA has a noticeable effect on the metalation of imines and their subsequent alkylation (eq 9).33 When the metalation (by s-Butyllithium) of an asymmetric imine is performed in THF, a subsequent alkylation gives about a 1:1 mixture of regioisomers. In the presence of HMPA, however, only the regioisomer due to alkylation at the less-substituted site was observed. A synthetically useful solvent effect for HMPA is also observed in the asymmetric synthesis of trimethylsilyl enol ethers by chiral lithium amide bases.34 The asymmetric induction in THF can be greatly improved by simply adding HMPA as a cosolvent.

    Carbanion Formation.

    Often substrates that cannot be metalated by LDA or n-Butyllithium in THF can be successfully deprotonated by adding HMPA as a cosolvent. Many other weakly acidic C-H acids, e.g. (1)-(6), can be successfully metalated in the presence of HMPA.35 HMPA also aids in the formation of dianions36 and increases the proton abstraction efficiency of Sodium Hydride.37,38

    Carbanion Reactivity.

    An increase in reaction rate is observed for the reaction of alkynyllithium reagents with alkyl halides3 and oxiranes39 (eq 10). The strongly coordinating HMPA probably complexes the lithium cation, thereby increasing the negative charge density on the carbon and creating a much more nucleophilic alkynyl anion. A similar effect is observed for (Trimethylstannylmethyl)lithium, which does not react with oxiranes in THF but in THF-HMPA the reaction proceeds readily.40

    The decarboxylation41 of 4-t-butyl-1-phenyl-1-carboxycyclohexane with Methyllithium gave a mixture of axial and equatorial products (eq 11), which was highly dependent on the nature of the solvent at the time of aqueous workup. Axial protonation was favored in ether-HMPA.

    HMPA is also the only dipolar aprotic solvent to be used extensively with organomagnesium compounds.42 Large effects are observed when HMPA is used as either a solvent or a cosolvent. As examples, HMPA accelerates addition of an allylic organomagnesium compound to aryl-substituted alkenes,43 addition of Grignard reagents to Carbon Monoxide,44 and addition of Propargylmagnesium Bromide to allylic halides to give allene products.45

    Carbanion Regioselectivity (1,2- vs. 1,4-Addition).

    The regioselectivity of addition of certain organolithium reagents to a,b-unsaturated carbonyl compounds is affected by the addition of HMPA. In the addition of 2-lithio-2-substituted-1,3-dithiane to cyclohexenone, there was a complete reversal of regioselectivity from 1,2-addition in THF to 1,4-addition with 2 equiv of HMPA present (eq 12).46

    Lithium reagents that exhibit kinetic 1,4-addition in HMPA are shown as (7)-(14).47 These include useful acyl anion equivalents48 like phenylthio(trimethylsilyl)methyllithium (see (Phenylthiomethyl)trimethylsilane).49

    A carboxy anion equivalent was reported to undergo 1,2-addition in the absence of HMPA;50 however, with 10 equiv of HMPA present only 1,4-addition was observed (eq 13). The addition of 1 equiv of HMPA promotes conjugate addition of alkyl and phenylthioallyl anions to cyclopentanones (eq 14) through the a-position, whereas in THF alone, irreversible 1,2-addition occurs with both a- and g-attack.51 The regioselectivities reported for the addition to cyclic enones of ketene dithioacetal anions47a,52 or t-Butyllithium (eq 15)53 are also influenced by HMPA (and counterion).

    Ylide Reactivity.

    HMPA is used as a cosolvent in the Wittig reaction to increase reaction rate, yield, and stereoselectivity. HMPA functions as a lithium cation-complexing agent and removes LiBr salt from ether solution (LiBr/HMPA complexes form precipitates in ether).54 Such a salt-free Wittig reaction mixture55 may be responsible for the high level of cis-alkene observed in reactions of nonstabilized ylides with aldehydes in THF or ether with added HMPA25,56 (eq 16). Similarly, increased (Z) selectivity is observed in the Wittig alkenation of 2-oxygenated ketones (eq 17) to generate protected (Z)-trisubstituted allylic alcohols.55,57

    With HMPA, Wittig reactions that give (E)-alkenes were also observed (eq 18),58 as was the directed selectivity of a semistabilized arsonium ylide towards carbonyl compounds. The arsenic ylide was generated from LDA in THF or THF/HMPA solution to give exclusively epoxide (eq 19) or diene (eq 20), respectively.59

    Nucleophilic Cleavage of Esters and Ethers.

    The conversion of hindered methyl esters to carboxylic acids, and the demethylation of methyl aryl ethers, can be effectively performed by using HMPA to increase the nucleophilicity of lithium methanethiolate.60 HMPA (or N,N-Dimethylformamide) will also facilitate the cleavage of methyl aryl ethers and their methylthio analogs by sodium methaneselenolate (see Methaneselenol) to give the phenol or thiophenol, respectively.60,61 Sodium ethanethiolate (see Ethanethiol) in refluxing DMF or HMPA attacks alkyl aryl selenides to give the corresponding diselenides. The most reactive combination of solvent and halide salt for the decarboxylation of b-keto esters was found to be Lithium Chloride/HMPA, used as part of a stereoselective synthesis of 11-deoxyprostaglandin E1.62 In HMPA, the rate of ester cleavage of 2-benzyl-2-methoxycarbonyl-1-cyclopentanone with Sodium Cyanide is 30 times as fast as the more commonly used DMF.62a

    Anion Reactivity.

    HMPA is one of the most potent electron pair donor solvents available for accelerating SN2 reactions.3,43a The formation, for example, of an a-silyl carbanion for use in a Peterson alkenation reaction63 can be accomplished by the displacement of silicon using Sodium Methoxide64 or Potassium t-Butoxide65 in HMPA (eq 21). The increased nucleophilicity of halide ions in the presence of HMPA is seen by the increased rate of silyl-protecting group removal with fluoride ion (Tetra-n-butylammonium Fluoride).66 The substitution of aryl chlorides can be performed using sodium methoxide in HMPA67 to give anisole derivatives, or by using sodium methanethiolate (MeSNa) (see Methanethiol) in HMPA61b,68 to generate either aryl methyl sulfides or aryl thiols, depending on the reaction conditions. The increased nucleophilicity of a magnesium alkoxide is demonstrated by the cyclization of a chloro alcohol to a 13-membered cyclic ether (eq 22) upon treatment of the compound with Ethylmagnesium Bromide in refluxing THF/HMPA.69

    The conversion of cyclic alkenes to 1,3-cycloalkadienes can be performed through a bromination/dehydrobromination procedure using LiCl/Lithium Carbonate/HMPA (eq 23).70 The dehydrobromination of 2,3-dibromo-3-methyl-1-butanol to generate a vinyl bromide has been accomplished through the use of 2.3 equiv of LDA and 0.5 equiv of HMPA in THF at -78 °C.71

    Low-Valent Metal Coordination (Lanthanoids).

    HMPA is used extensively as a solvent for dissolving-metal reductions.72 Used as a cosolvent (5-10%), it remarkably accelerates the one-electron transfer reduction of organic halides by Samarium(II) Iodide.73 The reductions work on a variety of primary, secondary, or tertiary halides, including chlorides which could not be reduced in pure THF (eq 24). The samarium Barbier reaction, which requires hours in refluxing THF, can be performed as a titration in THF-HMPA at rt (eq 25).74 The SmI2/THF/HMPA system has recently been used in the deoxygenation of organoheteroatom oxides,75 reductive dimerization of conjugated acid derivatives,76 and selective reduction of a,b-unsaturated carbonyl compounds.77 In addition, SmI2 was used in a tandem radical cyclization,78 and has been a useful reagent in Barbier-type reactions.73b,79 The dramatic acceleration of electron transfer is also observed for Ytterbium(0).80

    Transition Metal Coordination.

    The ability of HMPA to complex to metals and alter reactivity is also expressed in palladium-catalyzed coupling reactions. For example, ethylbenzene can be formed from the Pd0 catalyzed cross-coupling of Benzyl Bromide and Tetramethylstannane, with the formation of almost no bibenzyl.81 The reaction does not proceed in THF, but requires a highly polar solvent like HMPA or 1-Methyl-2-pyrrolidinone. Similarly, HMPA is necessary in the Pd0-catalyzed coupling of acid chlorides with organotin reagents to give ketones. In highly polar solvents like HMPA the transfer of a chiral group from the tin occurs with preferential inversion of configuration (eq 26).82 The relative rate of transfer of an alkynic or vinyl group to acid chlorides82a or aryl iodides83 is also greatly accelerated by HMPA. It can increase the rate of alkylation of p-allylpalladium chloride by ester enolates,84 and alter the chemoselectivity by leading to a cyclopropanation reaction instead of an allylic alkylation.85

    Hydride Reductions.

    The reduction of organic compounds by hydride can be influenced by the choice of cosolvent. Cyanoborohydrides (e.g. Sodium Cyanoborohydride) in HMPA provide a mild, effective, and selective reagent system for the reductive displacement of primary and secondary alkyl halides and sulfonate esters in a wide variety of structural types.86 A Sodium Borohydride/HMPA reagent system was used in the reduction of N,N-disulfonamides87 and in the reduction of dibromides to monobromides.37a Similarly, Tri-n-butylstannane/HMPA88 can be utilized to chemoselectively reduce aldehydes with additional alkene or halide functionality.89 Finally, the reduction of aldehydes and ketones with hydrosilanes proceeds in the presence of a catalytic amount of Bu4NF in HMPA.90 The reaction rate was much lower in DMF than in HMPA, and the reaction yields decreased considerably if less polar solvents like THF or CH2Cl2 were used.

    Oxidation.

    The oxidation of acid sensitive alcohols with Chromium(VI) Oxide in HMPA is one example of the use of HMPA in oxidation reactions.91 (CAUTION: Do not crush CrO3 prior to reaction since violent decomposition can occur. The use of DMPU has been reported to have a similar hazardous effect). Recently, a Bromine/NaHCO3/HMPA system92 was used for the oxidative esterification of alcohols with aldehydes, where the HMPA considerably accelerated the oxidation by bromine and lowered the rate of unwanted halogenation. Epoxidations of alkenes or allylic alcohols have been accomplished using MoO5.HMPA.pyridine (Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide); MoOPH).93

    Effect of HMPA on Protonation.

    The protonation of (9-anthryl)arylmethyllithium with various oxygen and carbon acids in THF or in THF-HMPA had a significant effect on the product ratio of C-a vs. C-10 protonation (eq 27).94 Another study95 found that a nitronate protonation led to mainly one diastereomeric product in a THF solution containing HMPA or DMPU (eq 28). Panek and Rodgers96 observed stereospecific protonation of 10-t-butyl-9-methyl-9-lithio-9,10-dihydroanthracene: >99% cis protonation was observed in THF or ether with greater than >99% trans protonation observed in HMPA.

    Inhibition by HMPA.

    Finally, it should be added that there are a few cases where HMPA slows the rate of a reaction. Such examples typically involved the inhibition of lithium catalysis by strong coordination of HMPA to lithium.97 For instance, two-bond 13C-13C NMR coupling in organocuprates is poorly observable in ether or THF at very low temperature.98 Exchange, however, is slowed in THF/HMPA or THF/12-crown-4, so that coupling is easily observed. The effect of HMPA suggests that Li+ is involved in the exchange process.

    HMPA Substitutes and Analogs.

    Researchers have searched for an alternative to HMPA. Such a solvent must be stable to polar organometallic compounds and be comparable to HMPA in its many functions. Replacement solvents typically are useful in some applications but have limited value in others. Examples of some useful alternatives are (15)-(19).30,42,99

    Chiral analogs of HMPA, (20)-(22), have been used as ligands in transition metal complexes.93b,100

    Related Reagents.

    N,N-Dimethylformamide; N,N-Dimethylpropyleneurea; Dimethyl Sulfoxide; Hexamethylphosphoric Triamide-Thionyl Chloride; Lithium Chloride-Hexamethylphosphoric Triamide; 1-Methyl-2-pyrrolidinone; Potassium t-Butoxide-Hexamethylphosphoric Triamide; Potassium Hydride-Hexamethylphosphoric Triamide; Potassium Hydroxide-Hexamethylphosphoric Triamide.


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    Robert R. Dykstra

    University of Wisconsin, Madison, WI, USA



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