Potassium Phosphate as a High-Performance Solid Base in Phase

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Potassium Phosphate as a High-Performance Solid Base in Phase-Transfer-Catalyzed Alkylation Reactions Nida Qafisheh,† Sudip Mukhopadhyay,‡ Ashutosh V. Joshi,† Yoel Sasson,*,† Gaik-Khuan Chuah,§ and Stephan Jaenicke§ Casali Institute of Applied Chemistry, The Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel, Department of Chemical Engineering, UniVersity of California, Berkeley, California 94720, and Department of Chemistry, National UniVersity of Singapore, Kent Ridge, Singapore 119260, Republic of Singapore

Potassium phosphate is reported as a remarkably active and selective solid base in phase-transfer-catalyzed alkylation reactions of alkaline-sensitive substrates such as esters and halides. The performance of potassium phosphate exceeded that of common bases such as hydroxides, carbonates, fluorides, and oxides. Even though potassium phosphate is not porous and the number of basic sites exposed at the surface is relatively low (0.05 mequiv/g), it is still fully consumed in the alkylation process and converted into K2HPO4. The heterogeneous process follows a second-order rate law, and the rate constant was found to depend strongly on particle size, presence of water in the system, thermal pretreatment of the base, structure of the phase transfer catalyst, nature of the solvent, and reaction temperature. Some surface properties of K3PO4 have been determined and are discussed with relevance to the above catalytic alkylation reactions. 1. Introduction The most significant achievement of phase transfer catalysis (PTC) in synthetic (mainly organic) chemistry has been the replacement of hazardous and humidity-sensitive bases such as sodamide, sodium hydride, or potassium tert-butoxide, with the milder and more robust sodium hydroxide (typically 50% w/w aqueous solution). With use of phase transfer systems, weakly acidic organic substrates with pKa as low as 38.41 could be deprotonated and reacted under mild hydrous conditions (e.g., in H/D exchange). The extraordinarily potent basicity was attributed to the combined effect2 of the heterogeneous acidbase equilibrium with the high selectivity coefficient in the extraction of the so-formed carbanion, oxanion, or azanions. The “interfacial mechanism” introduced by Makosza,3 after realizing that the free hydroxide ion is hardly extracted into the organic phase, is based on interfacial deprotonation of the organic acid ZH (C, N, O, or S acid) (step 1) followed by anion exchange and extraction of the organic anion as ion pair with the quaternary ammonium cation into the bulk organic phase (step 2) where it can react with added electrophiles:

Z-H(org) + NaOH(aq) h Z-Na+(int) + H2O

(1)

Z-Na+(int) + Q+X-(org) h Z-Q+(org) + Na+X-(aq)

(2)

Because step (2) removes the salt Z-Na+ from the interface, the equilibrium (1) is shifted to the right and the resulting basicity can be several orders of magnitude higher than the expected inherent basic strength of sodium hydroxide (hyperbasicity). Most applications of PTC/OH4 systems have been in C, N, O, and S alkylations. Typically, acidic substrates with pKa up to 24 are readily deprotonated by 50% aqueous NaOH in the presence of phase transfer catalysts5 and alkylated by various * To whom correspondence should be addressed. Phone: +972 26584530. Fax: +972 26529626. E-mail: [email protected]. † The Hebrew University of Jerusalem. ‡ University of California. § National University of Singapore.

alkyl halides or sulfonates. The phase transfer catalyst is most commonly a quaternary ammonium salt. Although never studied in detail, other types of phase transfer catalysts, such as poly(ethylene glycol)s (PEG) and crown ethers, are expected to behave similarly except that in step (2) there is no anion exchange but rather a complexation process where the salt Z-Na+ (or Z-K+) is coordinated and transferred as one unit into the bulk of the organic phase to react in the following step with a nucleophile. Notwithstanding the remarkable achievements of PTC/OH systems,6 some fundamental limitations still restrict the widespread use of this methodology. These are mainly related to the very presence of water in the hydroxide solutions. Water cannot be avoided in PTC/OH systems primarily due to the highly hygroscopic nature of NaOH and KOH (commercial batches of the latter contain up to 15% water). In addition, water may also form as a stoichiometric product in the successive alkylation process. Consequently, reactions under PTC/OH conditions are susceptible to competing hydrolytic reactions which are particularly evident with substrates such as esters,7,8 amides, and benzyl, allyl, or activated aryl halides.9 Another serious shortcoming of PTC/OH systems with onium salt catalysts stems from the inherent instability of these salts in alkaline environment due to the Hoffmann elimination.10 The latter is a destructive process which converts quaternary ammonium salts into tertiary amines and olefins. The decomposition is particularly rapid in concentrated NaOH or KOH solutions.11 This problem can be overcome if other phase transfer catalysts are used such as crown ethers or poly(ethylene glycol)s which are resilient to alkali. The highly corrosive nature of alkaline solutions toward glass and other materials poses further restrictions on these systems. One possible solution is the application of other milder anhydrous solid bases such as potassium or cesium carbonates,12 which are reasonably limited in their hydrolytic action (note that 0.5 mol of water is still released in the neutralization of the base, e.g., in alkylation reactions). Indeed, diethylmalonate has been smoothly and quite selectively (93% yield) monoalkylated with n-butyl bromide in the presence of anhydrous potassium carbonate and tetra-n-butylammonium bromide

10.1021/ie060899e CCC: $37.00 © 2007 American Chemical Society Published on Web 10/17/2006

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(TBAB).13 Cesium carbonate was recently applied for the PTC selective alkylation of thiols.14 Another approach is based on the unique basicity of the naked fluoride anion.15 KF has been used in organic synthesis either supported (mainly on Al2O316) or in phase transfer systems.17 Potassium phosphate was utilized as an auxiliary mild base in homogeneous metal-catalyzed processes, particularly in the presence of base-sensitive functional groups. Buchwald disclosed K3PO4 as an auxiliary base for the arylation of amides18 and ketones19 using copper or palladium catalysts. Potassium phosphate was also the base of choice in the Suzuki crosscoupling reactions of aryl triflates or halides and aryl boronic acids with Pd20 or Ni21 catalysts. Potassium phosphate has been recognized previously as a solid base which possesses unique highly basic sites, particularly when dehydrated upon calcination at 400 °C. Tada22 determined the basic strength of potassium phosphate as H0 ) 17.2 using acidic indicators and tested the catalytic activity for the decomposition of diacetone alcohol in the liquid phase at 3055 °C. Sodesawa et al.23 alkylated toluene to ethylbenzene over a potassium phosphate catalyst at 500 °C. Higuchi et al.24 examined the activity of potassium phosphate and other solid bases in the cyanosilylation of carbonyl compounds at 0 °C and measured 18.4 > H0 >15.0 after calcination of the phosphate at 180 °C. Li25 and later Al Shihiri26 applied potassium phosphate in the Knoevenagel condensation of cyanoacetates and malononitriles. In a related avenue, Zahouily et al.27 examined the catalytic properties of natural phosphate (fluoroapatite) and related or modified materials in solid-liquid basecatalyzed reactions. We have now realized that potassium phosphate, despite its relatively low basicity in aqueous medium (pKa of K2HPO4 is approximately28 12), is a very potent solid base in anhydrous systems and is substantially more active than potassium carbonate and potassium fluoride in the formation and subsequent reactions of carbanions, azanions, and oxanions.29 In several instances, solid K3PO4 outperformed even NaOH and KOH in reaction rate and selectivity. Upon neutralization (e.g., in alkylation reactions where the electrophile is alkyl halide), potassium phosphate does not generate water and reacts according to eq 3

HX + K3PO4 f KX + K2HPO4

(3)

where HX is a halide acid. In this study, we explore phase-transfer-catalyzed alkylation reactions, where potassium phosphate is used and consumed as a stoichiometric base. This category of reactions were reported previously by Li et al. who alkylated active methylene compounds with 2,3,4,6 tetra-O-acetylglycopyranosyl bromide using TBAB in acetonitrile30 and more recently by Wang et al. who have prepared thio-alkylated imidazole and triazole derivatives in the presence of anhydrous potassium phosphate in acetone.31 2. Experimental Section Potassium phosphate, tribasic, anhydrous (purity 98%), was purchased from Aldrich. Phase transfer catalysts and all reagents were also purchased from Aldrich with purity >98% and used as received. Solvents were dried by standard procedures. General Procedure for the Alkylation of Diethylmalonate with 1,2-Dibromoethane. To a 100 mL round-bottom glass reactor equipped with a reflux condenser and an efficient mechanical stirrer placed in an isolated thermostatic bath the following materials were added: 1.6 g of diethylmalonate (10

Table 1. Effect of Different Solid Bases on the Reaction Presented in eq 4a entry

base

time, h

% conversion

1 2 3 4

K3PO4 K2CO3 KOH KF

4 2, 4, 8 1, 2, 4 4, 8

94 15, 25, 40 67, 90, 98 7, 18

a Reaction conditions: Diethylmalonate, 10 mmol; 1,2-dibromoethane, 30 mmol; base, 25 mmol; 18-crown-6, 0.5 mmol; DMA, 40 mL; temperature, 70 °C; agitation speed, 900 rpm.

mmol), 5.67 g of 1,2-dibromoethane (30 mmol), 5.4 g of anhydrous potassium phosphate (25 mmol, average particle size 420 µm), 132 mg of 18-crown-6 (0.5 mmol), 40 mL of dry dimethylacetamide, and (if required) 0.1 mL of biphenyl as internal standard. The mixture was maintained at 70 °C with vigorous stirring (900 rpm). The progress of the reaction was monitored by analysis of samples using gas chromatography. In preparative preparation, the reaction mixture was filtered after 100% conversion was attained, and the filtrate was diluted with 100 mL of methylene chloride and washed several times with water. The organic phase was dried over magnesium sulfate and evaporated, under vacuum, to remove the methylene chloride and the excess of 1,2-dibromoethane to yield 1.7 g of 1,1-cyclopropane dicarboxylate diethylester, purity 95% (90% yield). Quantitative and qualitative analyses were performed using an HP-5890 gas chromatograph equipped with a 50% diphenyl50% dimethylpolysiloxane 25 m/0.53 mm capillary column and an FID detector. The GC injection program was as follows: initial temperature 50 °C, (2 min), ramp at 10 °C/min, final temperature 280 °C. Helium was used as the carrier gas at pressure of 50 kPa. GC was calibrated using biphenyl as internal standard. Products were identified by comparison to authentic samples. Surface areas were determined with a Micromeritics Tristar 3000 Gas Adsorption Analyzer. Temperature-programmed desorption of CO2 was measured with a home-built instrument using a Balzers Prisma quadrupol mass spectrometer for detection. XRD spectra were recorded with a Bruker AXS D8 Advance instrument with Cu KR radiation (λ ) 154.06 pm). The diffractometer is set up with theta-theta (θ-θ) geometry and a stationary horizontal sample holder. The sample is contained in a high-temperature oven with Kapton windows and can be kept in a vacuum or a controlled atmosphere. Measurements were taken during a temperature scan up to a maximum temperature of 1000 °C. 3. Results and Discussion 3.1. Alkylation of Diethylmalonate in the Presence of Different Bases. We have initially examined the performance of different solid bases in the phase-transfer-catalyzed double alkylation of diethylmalonate (pKa )13.3) with 1,2-dibromoethane to yield cyclopropane-1,-diethyldicarboxylate (reaction 4). The reaction was performed at 70 °C in dimethylactetamide (DMA) as a solvent. Table 1 presents the conversion obtained in reaction 4 after 1-8 h using potassium phosphate, potassium hydroxide, potassium carbonate, and potassium fluoride as bases and 18-crown-6 as catalyst.

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No attempt was made to dehydrate the solid bases and they were all used as received from the supplier. The selectivity of reaction 4 was found to be 100% in the experiments with KF, K2CO3, and K3PO4, but with KOH approximately 10% hydrolysis of the ester groups of the product and of the starting material was observed. Attempts to promote reaction 4 with other bases such as magnesium or calcium oxides under the conditions of Table 1 did not succeed, and the starting materials were fully recovered. The remarkable results summarized in Table 1 clearly suggest that K3PO4 outperforms KF and K2CO3 in reaction 4 and is very close in activity to the much stronger base KOH. Nonetheless, the latter suffers from competing hydrolytic reactions rendering potassium phosphate as the base of choice for these and related transformations. Identical trends were found with other alkylating agents such as benzyl chloride and 1-bromopentane. Again, competing hydrolytic and/or elimination reactions of the latter substrates were also observed when KOH was used as a base. The outstanding advantage of potassium phosphate over the stronger, more common bases was preserved also when conventional heating was replaced by microwave irradiation in a solvent-free system. The rate of reaction 4 under microwave irradiation using different bases decreased in the order K3PO4 > K3PO4‚3H2O > KOH > K2CO3 > t-BuOK > NaOH > KF. Again, the presence of a phase transfer catalyst was determined to be crucial. The stoichiometry and the mass balance of the process using K3PO4 as a base were confirmed to be according to eq 5: After

completion of the reaction, water was added, and the amount of KBr was assayed by argentometric titration. The presence of K2HPO4 as the sole phosphate product was confirmed by 31P NMR using D O solvent (2.73 ppm as compared with 0.18 2 ppm for KH2PO4 and 3.03 ppm for K3PO4). The intermediate monoalkylation product (2-bromoethyl diethylmalonate) could not be detected in our tests, indicating a fast cyclization step in comparison with the first slower alkylation stage. The stirring rate had some effect on the progress of reaction 5 in our 100 mL reactor but only up to a rate of 400 rpm. Subsequent experiments were thus all carried out with mechanical stirring at 900 rpm where mass transfer does not limit the process. 3.2. Comparison of Different Solvents and PT Catalysts. Other phase transfer catalysts were found to be less effective than 18-crown-6. Figure 1 portrays the conversion (identical to yield) of reaction 5 after 8 h of stirring at 70 °C in toluene as solvent in the presence of various phase transfer catalysts. The obvious conclusion is that the PT catalyst is essential for obtaining a useful reaction rate and that 18-crown-6 is the catalyst of choice out of the list tested. Interestingly, the performance of the symmetrical quaternary salt TBAB and of the surface-active agent CTAB is essentially identical despite the difference in the nature of these catalysts. Toluene was found to be inferior to the more polar DMA, but better than dioxane where the reaction rate was approximately half that in toluene. On the other hand, dimethyl sulfoxide (DMSO) demonstrated outstanding activity as a solvent with initial rate in reaction 5 an order of magnitude higher than in DMA.

Figure 1. PTC effect on the reaction presented in eq 5. Reaction conditions: Diethylmalonate, 10 mmol; dibromoethane, 30 mmol; potassium phosphate, 20 mmol; PTC, 0.5 mmol; toluene, 10 mL; temperature, 70 °C; agitation speed, 900 rpm; reaction time, 8 h.

Figure 2. Effect of potassium phosphate average particle size on reaction rate (eq 5). Reaction conditions: Diethylmalonate, 10 mmol; dibromoethane, 30 mmol, potassium phosphate, 25 mmol; 18-crown-6, 0.5 mmol; DMA (solvent), 40 mL; temperature, 70 °C; agitation speed, 900 rpm.

3.3. Effect of Temperature and Potassium Phosphate Particle Size. For a given catalyst concentration reaction 5 was found to follow a second-order rate equation. The rate is firstorder with respect to both the diethylmalonate concentration and the 1,2-dibromoethane concentration. The concentration of the solid potassium phosphate can be assumed constant and is not changing with time. However, we predicted that the surface area of the phosphate will have a formidable effect on the reaction rate. Thus, commercial potassium phosphate was ground and sieved into three batches with average size of 420505 µm, 505-595 µm, and 595-707 µm. The average diameter of the particles in these samples was calculated as 420, 550, and 595 µm, respectively. Reaction 5 was then performed at 70 °C with each of these batches under otherwise identical conditions. Figure 2 presents these reaction profiles plotted as second-order graphs for each run. The calculated second-order constants are 0.0657, 0.0166, and 0.0026 dm3 mol-1 min-1, respectively. These results suggest a very strong dependence of the reaction rate on the particle size (and surface area) of the base. This indicates the critical role that the surface properties play in the reaction mechanism. In the next set of experiments we examined the effect of temperature on the rate of reaction 5 using potassium phosphate particles with average diameter of 550 µm. Figure 3 presents the conversion-time profiles of the reaction carried out at different temperatures plotted as second-order reactions. We calculated the second-order rate constants to be 0.006, 0.021, 0.068, and 0.210 dm3 mol-1 min-1 at 20, 45, 70, and 90 °C, respectively. The corresponding activation energy is 46.6 kJ/ mol, which is a typical value for a chemically controlled process with minimal mass transfer resistance. 3.4. Effect of Water and Thermal Pretreatment on K3PO4 Activity. The critical effect of traces of water on solid-liquid

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Figure 3. Determination of the reaction rate equation and effect of temperature (reaction 5). Reaction conditions: Diethylmalonate, 10 mmol; dibromoethane, 30 mmol; potassium phosphate, 25 mmol (size 420 µm); 18-crown-6, 0.5 mmol; DMA, 40 mL; temperature, 70 °C; agitation speed, 900 rpm.

Figure 4. Effect of the amount of added water on the alkylation reaction (reaction 5, conversion after 4 h). Reaction conditions: Diethylmalonate, 10 mmol; 1,2-dibromoethane, 30 mmol; anhydrous potassium phosphate, 25 mmol; 18-crown-6, 0.5 mmol; DMA, 40 mL; temperature, 70 °C; agitation speed, 900 rpm; reaction time, 4 h; % water (in wt % based on K3PO4 weight).

phase transfer reactions has been studied in detail by several groups.32 In studying reaction 5 we verified that the presence of water inhibits the alkylation process. The conversion in reaction 5 after 4 h obtained with the addition of varying amounts of water to the reacting mixture is shown in Figure 4 as wt % relative to potassium phosphate. It is apparent that surface water retards the reaction, probably via restriction of the access of the substrate to the basic sites and partially by neutralizing the latter, resulting in slower reaction rate. The opposite trend was realized upon calcination of the potassium phosphate (with average particle size 595 µm) for 6 h at temperatures of 200, 400, and 600 °C. This pretreatment dramatically affected the reaction rate of reaction 5. Results are presented in Figure 5, where reaction profiles (plotted as secondorder reactions) are shown for different pretreatment temperature of the potassium phosphate used. An order of magnitude increase in the second-order rate constant is evident upon calcination of potassium phosphate at 600 °C in comparison with the untreated base. The measured rate constants are 0.017, 0.037, 0.010, and 0.165 dm3 mol-1 min-1 for the untreated material, and for potassium phosphate pretreated at 200, 400, and 600 °C, respectively. Atomic force microscopy (AFM) images of the potassium phosphate samples before and after heat treatment at different temperatures are shown in Figure 6 a-d. A transformation in the surface morphology of the surface is apparent with a noticeable decrease in exterior crystallite size. Prior to heat treatment, the material displays well-formed crystals with a smooth surface and an average diameter of approximately 1250

Figure 5. Effect of calcination temperature on the reaction rate (reaction 5). Reaction conditions: Diethylmalonate, 10 mmol; 1,2-dibromoethane, 30 mmol, potassium phosphate, 25 mmol (average particle size 595 µm); 18-crown-6, 0.5 mmol; DMA, 40 mL; temperature, 70 °C; agitation speed, 900 rpm.

nm. After calcination at 600 °C, the surface roughens, and the feature size decreases to 200 nm. Interestingly, the modifications of the surface with calcination are evidently limited only to the exterior part of the potassium phosphate particles. XRD did not show any crystallographic or morphological changes upon heating. At temperatures below 300 °C, various hydrated phases are found. At higher temperature, the only phase detected is K3PO4 (cubic). This is shown in Figure 7. We initially assumed that the heat treatment leads to an increase in the number and strength of the basic sites. This hypothesis could not be confirmed. Temperature-programmed desorption (TPD) of CO2 from potassium phosphate treated to different temperatures clearly demonstrated that the number and the strength of the basic sites decreases with the calcination process. This is apparent from Figure 8, where desorption curves for samples pretreated at 300, 400, 500, and 600 °C and for a nontreated material are compared. The area under the curves decreases, and a new desorption peak at lower temperature, indicating a weaker base strength, appears for material pretreated to the higher calcination temperatures. In Figure 9, the number of basic sites per g of K3PO4 is shown as a function of the calcination temperature. The surface area of the heat-treated potassium phosphate samples was determined by nitrogen adsorption. The untreated phosphate has a surface area of 2.22 m2 g-1. After the phosphate was heated to 200 and 600 °C, the surface area was 3.39 and 4.56 m2 g-1, respectively. This increase in surface area, accompanied by change in surface morphology, can be the rationale for the dramatic increase in activity observed after calcination of the potassium phosphate. There is also the possibility that upon handling of the anhydrous potassium phosphate in normal atmosphere, rapid hydration of the surface takes place. It was indeed observed that upon standing in open air in our laboratory, a sample of potassium phosphate gained 1% in weight within 10 min. This means that a very thin film of hydrated phosphate forms on the surface, which affects the surface basicity and probably other properties. Calcination evidently removes this thin layer of hydrates, resulting in an increase of activity. Further substantiation of this notion could be found in the thermal gravimetric analysis of potassium phosphate sample. The TGA of a sample that was finely ground in an inert atmosphere but exposed to air during loading into the sample pan is shown in Figure 10. It can be seen that major water loss occurs between 100 and 200 °C while at higher temperature the rate of weight loss is slower. Until 400 °C a loss of three molecules of water is observed, indicating that, on exposure to the atmosphere, the material had been rapidly hydrated to a

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Figure 6. (a) Untreated potassium phosphate sample. (b) Potassium phosphate calcined at 200 °C. (c) Potassium phosphate calcined at 400 °C. (d) Potassium phosphate calcined at 600 °C.

Figure 7. Effect of heating on K3PO4 crystal structure by XRD analyses.

formula close to K3PO4‚3H2O. The loss of this water leads to the changes in surface morphology that were seen in the AFM micrographs. The roughened surface is obviously much more reactive and can be more easily dissolved by the PTC; this effect is not restricted to a surface layer, but influences the dissolution kinetics of the entire particle. 3.5. Other K3PO4 Promoted Reactions Under Phase Transfer Conditions. Other less acidic substrates could likewise be alkylated under the same conditions. Thus, benzyl cyanide (pKa ) 22) and deoxybenzoin (pK ) 16) were smoothly

alkylated by n-pentyl bromide (with the latter substrate some O-alkylation was also observed). Fluorene (pKa ) 23) was inert in the presence of K3PO4, although in the presence of air, rapid autoxidation did take place (eq 6):

A much weaker carbon acid that was evidently deprotonated by potassium phosphate is allyl benzene (pKa ) 34). At

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Figure 8. TPD spectra of thermally treated potassium phosphate samples. Each sample is heated to the desired temperature and then allowed to cool, exposed to CO2, and heated again at a controlled rate to desorb the adsorbed CO2. The black line corresponds to untreated K3PO4 for which the scale is multiplied by 10.

Figure 9. Surface concentration of strong basic sites on K3PO4 pretreated at different temperatures as determined by temperature-programmed desorption (TPD) of CO2.

Figure 10. TGA curve for freshly ground potassium phosphate (particle size 90-110 µm) after short exposure to air.

100 °C in DMSO as solvent in the presence of K3PO4 and 18crown-6 (both in catalytic quantities), allyl benzene was promptly converted to the equilibrium mixture of 19% cis-βmethylstyrene, 80% trans-β-methylstyrene (eq 7). K3PO4, 18-crown-6

PhCH2CHdCH2 9 8 PhCHdCHCH3 DMSO, 100 °C

(7)

Reaction 7 proceeds through the formation of a carbanion intermediate. We recently described two other potassium phosphate promoted reactions, the nucleophilic chlorination of symmetrical tetrachloropyridine using carbon tetrachloride as a chlorinating agent,33 and the autoxidation of thiols to disulfides.34 3.6. Proposed Mechanism. Based on our results, we can presume that the phase transfer process described in eq 5 follows a mechanism similar in nature to the interfacial mechanism proposed in 1975 by Makosza35 for liquid-liquid systems. Since we did not find any trace of phosphate anion (based on 31P NMR) in any of the solvents we have examined in this study (combined with different phase transfer catalysts), we can safely argue that phosphate is not extracted into the organic phase either as a potassium salt or as any other ion pair. Given that our solvent (DMA) is not basic in nature, we can neglect acidbase interaction between potassium phosphate and the solvent. This might not be the case when DMSO was used as a solvent and is definitely not the case when alcohols are applied as solvents. We have positively proven that upon contacting ethanol with potassium phosphate in the absence, and particularly in the presence, of various phase transfer catalysts, a significant amount of basicity is transferred to the organic phase. Again, no phosphorus was detected in the liquid phase. We therefore conclude that ethanol is being deprotonated on the surface of the potassium phosphate, and potassium ethoxide is extracted into the bulk ethanol. This can be the rationale for the outstanding activity of alcohols in reactions catalyzed by phosphates such as Knoevenagel and Michael reactions.29 It can probably also explain the exceptional activity of the weakly acidic DMSO as a solvent in reaction 5, although it should be noted that we have not observed any alkylation products of DMSO in our reaction mixtures (this could have indicated the presence of DMSO deprotonation products). For that reason, alcohols cannot be considered as solvents for alkylation reactions such as reaction 5. In the absence of an acidic solvent, the substrate is deprotonated on the surface of the base, creating ion pairs with potassium cations. The latter are then extracted by the PT catalyst to the bulk organic phase were they encounter the electrophilic 1,2-dibromoethane and react in two consecutive alkylation steps to release two molecules of KBr and the product.

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Figure 11. Proposed mechanism of a crown ether phase-transfer-catalyzed alkylation reaction in the presence of solid potassium phosphate.

We could not identify any poisoning effect of KBr on reaction 5, so we can conclude that the latter does not deposit on the surface of the phosphate, where it would block access to the active sites for the ion exchange. With a given amount of potassium phosphate and PT catalyst, the reaction was observed to follow second-order kinetics. We therefore conclude that the rate-determining step is the homogeneous reaction between the nucleophile and the electrophile in the liquid phase. This is supported by the relatively high apparent activation energy, which is atypical for masstransfer controlled reactions, and by the lack of any effect of the stirring rate above 400 rpm. Interestingly, the potassium phosphate was completely consumed in these solid/liquid systems when it was present in a stoichiometric amount. This indicates that the product, potassium bromide, is not directly precipitated on the surface of the phosphate particles, where it would block the access of the substrate to the catalyst. New basic sites are evidently continuously exposed and react as the reaction proceeds, with the solid products KBr and K2HPO4 not interfering with the process. The shrinking size of the potassium phosphate particles with the progress of the reaction resulting in decreasing surface area also did not affect the reaction rate, again suggesting that the interaction of the substrate with the surface basic sites is very fast and does not limit the overall reaction rate. Unlike the critical role of traces of water in other solid-liquid phase transfer reactions,32 where rates were slowed or totally halted when the system was totally dried out, K3PO4 activity was continuously increasing with dehydration. Figure 11 presents our proposed catalytic cycle for the crownether phase-transfer-catalyzed alkylation reaction using potassium phosphate as solid base. 4. Conclusions Anhydrous potassium phosphate is a mild and safe but very effective solid base that is more potent than common solid bases such as carbonates, oxides, or fluorides and is also more reactive and selective in certain reactions than KOH or NaOH. We believe that the methodology described here can be effortlessly developed into numerous synthetic applications in laboratory and also on industrial scale. Literature Cited (1) Feldman, D.; Rabinovitz, M. Reactions of Weak Carbon Acids Under Phase Transfer Catalysis Conditions - Oxidation and Hydrogen-Deuterium Exchange. J. Org. Chem. 1988, 53, 3779.

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ReceiVed for reView July 12, 2006 ReVised manuscript receiVed August 26, 2006 Accepted September 1, 2006 IE060899E