Phosphazene Base P4-t-Bu

[111324-04-0]  · C22H63N13P4  · Phosphazene Base P4-t-Bu  · (MW 633.86)

(extremely strong, highly hindered, kinetically highly active base;1 generates exceptionally nucleophilic naked carbanions from a wide range of carbon acids;2 the very low Lewis acidity of the cation suppresses side reactions commonly observed with metal organyls, e.g. aldol and ester condensations3 and b-eliminations4)

Alternate Name: 3-t-butylimino-1,1,1,5,5,5-hexakis(dimethylamino)-3-{[tris(dimethylamino)phosphoranylidene]amino}-1l5,3l5,5l5-1,4-triphosphazadiene.

Physical Data: mp ca. 207 °C (dec); pKBH+ 30.1.5

Solubility: very sol THF, ether, hexane, benzene, toluene; sol with protonation in protic solvents, MeCN; reacts rapidly with all types of haloalkanes except fluoroalkanes.

Form Supplied in: 1 M solution in hexane; commercially available.

Analysis of Reagent Purity: NMR in benzene-d6. 1H NMR: d 1.83 (s, 9 H), 2.73 (d, J = 10 Hz, 54 H); 13C NMR: d 35.6 (br d, J &AApprox; 13 Hz), 38.08 (d, J = 4 Hz), 51.31 (d, J = 5.5 Hz); 31P NMR: d -24.44 (q, J = 20 Hz), 5.74 (br m).

Purification: all water-soluble salts of P4-t-Bu can be converted to the HBF4 salt by precipitation from aqueous solution with NaBF4. Water-insoluble salts are first converted to the chloride by means of a column charged with strongly basic anion exchange resin (Cl- form, MeOH). P4-t-Bu.HBF4 is recrystallized from aqueous ethylamine and dried in vacuo at 60 °C. 2.35 g (60 mmol) of potassium metal and 5 mg of Fe(NO3)3.9H2O are added to 50 mL of anhydrous NH3(l) with stirring (glass-covered stirring bar) under N2 and the solution kept at ca. -40 °C until the color turns to gray and evolution of H2 ceases. A solution of 21.6 g (30.0 mmol) of P4-t-Bu.HBF4 in 50 mL of THF is added and the mixture stirred at -40 °C for another 15 min. After evaporation of solvents in vacuo, the residue is extracted with 60 mL of hexane (caution! KNH2 is pyrophoric), rigorously protecting from moisture. The solvent is removed at reduced pressure, affording up to 18.3 g (96%) of the crystalline base. P4-t-Bu can be sublimed at 160 °C/10-3 mmHg, but protic impurities are not removed thereby.

For most applications, P4-t-Bu must be strictly anhydrous, but water content is not readily detected by NMR. The following procedure has proven to be effective in the elimination of small amounts of protic impurities: to a 0.5 M solution of the base in hexane or heptane, ethyl bromide (at least 3 mol per mol of H2O) is added. After 0.5 h at rt, diethyl ether and excess ethyl bromide (bp 31 °C) are removed by evaporating part of the solvent in vacuo, the precipitated hydrobromide salt of the base is filtered off, the solvent is removed completely in vacuo, and the residue is dried in a high vacuum.

Handling, Storage, and Precautions: P4-t-Bu is extremely hygroscopic and must be stored and handled so as to rigorously exclude moisture. It is thermally stable up to ca. 120 °C, extremely resistant towards (basic) hydrolysis, and likewise insensitive to dry oxygen.

Alkylations of Carbanions.

P4-t-Bu is a member of a novel class of kinetically highly active uncharged bases,1,2,6-8 with pKBH+ values ranging from 135,6 to ca. 34;1,2,5,7,8 among the strongest of these phosphazene bases, it is the most readily available.1 In the presence of alkylating agents, in situ alkylation of low acidic substrates in concentrated (ca. 0.5 M) THF solution is generally extremely rapid on (gradual) addition of P4-t-Bu at -100 °C to -78 °C. Due to the high solubilizing power of phosphazene bases, solubility problems are scarce. Separation of products from salts of the base is easily achieved, e.g. by direct precipitation of its halide salts with diethyl ether or benzene, by extraction (CH2Cl2) or precipitation (NaBF4) of salts from aqueous solution, or by filtration over silica gel. The very low Lewis acidity of the huge cation contrasts sharply with the characteristics of lithium amide bases. Thus Lewis acid-catalyzed side reactions, e.g. aldol or ester condensations in alkylations of enolates, are effectively suppressed; even b-lactones are easily mono-2 or peralkylated (eq 1).8 In cases where the corresponding lithium organyls decompose entirely via b-alkoxide elimination,4,9 naked enolates of b-alkoxy esters undergo clean alkylation.

Using more hindered bases like P4-t-Oct2,7,10 (t-Oct = 1,1,3,3-tetramethylbutyl) enhances the selectivity for monoalkylation considerably (eq 2).2 This tendency also holds for selective monoalkylation of secondary carbon centers.8 Even sterically congested quaternary centers are formed with great ease (eq 3).4

Alkylation of nitriles is not complicated by Thorpe condensation, as observed with Lithium Diisopropylamide as base. Alkylation of 1,2-dinitriles with no elimination of hydrocyanic acid (eq 4)8 is achieved in high yield.

Alkylation of Nitrogen Acids.

N-Perbenzylation of rather insoluble N-Boc-protected or cyclic peptides leads to easily soluble, fully protected derivatives.11 Occasionally, regioselective C-alkylation of glycine or sarcosine subunits is also observed (eq 5).

Anionic Polymerization.

Polymerization of methyl methacrylate occurs in the presence of P4-t-Bu. Using ethyl acetate as initiator in THF at elevated temperatures, high molecular weights and narrow molecular weight distributions are achieved,3 back-biting by ester condensation12 being effectively suppressed. Presumably due to lack of chelate control by the cation, the stereochemistry differs from that of polymerizations with metal organyls, syndiotactic diads being favored (eq 6).

Other Applications.

The high steric hindrance of P4-t-Bu enables the formation of isomerically pure 1-alkenes from primary halides at rt in almost quantitative yield.1 The simplicity of the NMR spectra, the UV transparency (end absorption below 230 nm), and the simplicity of handling recommends P4-t-Bu and other phosphazene bases for obtaining spectroscopic data of highly basic or unstable naked anions.13

Related Commercially Available Bases.

A number of other phosphazene bases are commercially available. P1-t-Oct (1), P1-t-Bu (2), BEMP (3), BEMP bound to a Merrifield polymer, and BTPP (4)10 are hindered bases, suitable for O-alkylation of carbohydrates6,14 and cyanohydrins,6 N-alkylation of nucleosides6 and carbamates,15 C-alkylation of alkyl malonic esters,6 O-tosylation of amino alcohols,16 and aldol condensations;17 reactions with these bases are often considerably more selective than with metal bases.

N-Alkylation of phthalimide (Gabriel synthesis) occurs in homogeneous acetonitrile solution at rt.18 In contrast to DBU or guanidines, all phosphazene bases are highly resistant towards basic hydrolysis, thus representing easy-to-recover catalysts for the basic hydrolysis of sensitive esters in a relatively apolar medium (eq 7).19

P2-Et (5)10,20 is only a moderately hindered base (pKBH+ = 20.2),5 suitable for E2 elimination reactions of secondary halides, which is ca. 4 orders of magnitude more reactive and less easily alkylated than DBU (pKBH+ = 11.8).5

Related Reagents.

1,1,1,3,3,3-Hexakis(dimethylamino)-1l5,3l5-diphosphazenium Fluoride.


1. Schwesinger, R.; Schlemper, H. AG(E) 1987, 26, 1167.
2. Schwesinger, R. Nachr. Chem. Tech. Lab. 1990, 38, 1214 (CA 1991, 114, 23 099a).
3. Pietzonka, T.; Seebach, D. AG(E) 1993, 32, 716.
4. Pietzonka, T.; Seebach, D. CB 1990, 124, 1837.
5. The relative pKa value of the conjugate cation in MeCN, based on 9-phenylfluorene = 18.49; values beyond 22 are extrapolated from a THF scale.
6. Schwesinger, R. C 1985, 39, 269.
7. Schwesinger, R.; Hasenfratz, C.; Schlemper, H.; Walz, L.; Peters, E.-M.; Peters, K.; von Schnering, H. G. AG(E) 1993, 32, 1361.
8. Schwesinger, R.; Hasenfratz, C. Unpublished results.
9. Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R. H 1987, 70, 1194.
10. Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller, M.; Schmitt, D.; Fritz, H. CB 1994, 127, 2435.
11. Pietzonka, T.; Seebach, D. AG(E) 1992, 31, 1481.
12. Posner, G. H.; Shulman-Roskes, E. M. JOC 1989, 54, 3514.
13. Fletschinger, M.; Zipperer, B.; Fritz, H.; Prinzbach, H. TL 1987, 28, 2517; Gais, H.-J.; Vollhardt, J.; Krüger, C. AG(E) 1988, 27, 1108; Braun, J.; Hasenfratz, C.; Schwesinger, R.; Limbach, H.-H. AG(E 1994, 33, 2215.
14. Netscher, T.; Schwesinger, R.; Trupp, B.; Prinzbach, H. TL 1987, 28, 2115; Sproat, B. S.; Beijer, B.; Iribarren, A. Nucleic Acid Res. 1990, 18, 41.
15. Schubert, J.; Schwesinger, R.; Knothe, L.; Prinzbach, H. LA 1986, 2009; Kühlmeyer, R.; Seitz, B.; Weller, T.; Fritz, H.; Schwesinger, R.; Prinzbach, H. CB 1989, 122, 1729; Falk-Heppner, M.; Keller, M.; Prinzbach, H. AG(E) 1989, 28, 1253.
16. Prinzbach, H.; Lutz, G. Unpublished results.
17. Montforts, F. P.; Schwartz, U. M. AG(E) 1985, 24, 775.
18. Schwesinger, R. Unpublished results.
19. Schwesinger, R.; Willaredt, J. Unpublished results.
20. Schwesinger, R.; Schlemper, H. Unpublished results.

Reinhard Schwesinger

University of Freiburg in Breisgau, Germany



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