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Key Role of Water for Nucleophilic Substitutions in Phase-Transfer-Catalyzed Processes: A Mini-Review Domenico Albanese, Dario Landini,* Angelamaria Maia, and Michele Penso Centro CNR and Dipartimento di Chimica Organica e Industriale dell’Universita` , via Venezian 21, I-20133 Milano, Italy
The fundamental role of water in anion-promoted reactions carried out under both liquid-liquid and solid-liquid phase-transfer catalysis (LL- and SL-PTC, respectively) conditions is reviewed. In particular, the hydration effect on the quaternary onium salt extraction constants, anion selectivity coefficients, and anion reactivity under LL-PTC conditions is reported. The effect of added water on SL-PTC reaction rates is also included. In addition, guidelines for optimizing the amount of water in the application of PTC to organic synthesis are proposed. Introduction In anion-promoted reactions performed under both liquid-liquid and solid-liquid phase-transfer catalysis (LL- and SL-PTC, respectively) conditions, water is found to have a profound effect in determining (i) the partition of the catalyst, (ii) the activation of the reactant anion, (iii) the anion selectivity coefficients, and (iv) the ion exchange between the solid salt and the catalyst.1,2 The major role played by water in a number of selected phase-transfer processes and its optimization, very important for industrial applications, are reviewed here. Effect of Water on the Catalyst Partition under LL-PTC Conditions (EQX) Liquid-liquid phase-transfer catalysis (LL-PTC), characterized by an aqueous phase containing the salt source of the anionic reagent and an immiscible organic phase, is the most widely utilized system for carrying out phase-transfer-catalyzed reactions.1,2 Fundamental requirements for such a process are (a) an efficient transfer of the reacting anion X-, as a Q+X- ion pair, from the aqueous to the organic phase, where it reacts with the substrate; and (b) a quantitative and selective release of the product anion Y- from the organic to the aqueous phase to continue the catalytic cycle (Scheme 1). It has been found that, for a process limited by the intrinsic reaction rate (kI , kT), the catalytic activity of a phase-transfer agent is directly related to its concentration in the organic phase.1,2 The exchange of the reactant (X-) and product (Y-) anions does not require the concomitant partition of the cation Q+ into the aqueous phase.2b As a consequence, other conditions being the same, the highest catalytic activity is achieved when Q+ is completely partitioned in the organic phase associated with the reacting anion X-.2b High extraction constant values EQX (defined by eq 1) are obtained by using long-chain lipophilic quaternary onium cations * Author to whom correspondence should be addressed. E-mail:
[email protected].
Scheme 1. Schematic Representation of a LL-PTC SN2 Substitution Reaction
(hexyl4N+, octyl4N+, etc.). EQX
X-(aq) + Q+(aq) y\z Q+X-(org) kI
(1)
Q+X-(org) + RY(org) 98 RX(org) + Q+Y-(org)
(2)
Q+Y-(org) h Q+(aq) + Y-(aq)
(3)
Alternatively, it is possible to use medium size quaternary cations, such as Bu4 N+, and to still have a high concentration of catalyst Q+X- in the organic phase by reducing the quantity of water and simultaneously increasing the aqueous concentration of the inorganic salt MX, the source of the reacting anion X-.3 In the nucleophilic substitution reaction of n-octyl methanesulfonate with bromide (reaction 4) in a chlorobenzenewater two-phase system the catalytic activity of Bu4N+Br- was found to increase by 20 times as the aqueous KBr concentration was increased from 1 to 6 M. Q+X-(cat)
n-C8H17OSO2Me(org) + MX(aq) 98 n-C8H17X(org) + MMeSO3(aq) (4) Q+ ) C16H33P+Bu3, Bu4N+, hexyl4N+ M ) Na, K X- ) F-, Cl-, Br-, I-, N3-, CN-, SCN-, PhO-, PhSSuch enhancement was mainly attributed to the more favorable partition coefficient EQX (salting out) of the
10.1021/ie0008124 CCC: $20.00 © 2001 American Chemical Society Published on Web 04/26/2001
Ind. Eng. Chem. Res., Vol. 40, No. 11, 2001 2397 Table 1. Hydration State n of Anions Associated with Quaternary Cations in Low-Polarity Solvents in Aqueous-Organic Two-Phase Systems (Q+X-‚nH2O) C16H33P+Bu3X-
(C8H17)4N+X-
X-
chlorobenzene2
1-cyanooctane6
toluene7
OHFClBrICNNO3N3SCNPhOPhCH2COOPhCOOPhS-
11 8.5 3.4 2.1 1.0 5.0 3.0 2.0 5.0 4.0 4.0 5.0 2.7
4.0 5.0 -
3.2 2.4 -
catalyst in the organic phase.3 Similarly, in the reaction of thiophenoxide ion with 1-bromooctane carried out under LL-PTC conditions the addition of NaBr (0.5 M) caused an 8-fold increase in the catalytic efficiency of cetyltriethylammonium bromide in comparison with the salt-free conditions.4 Finally, the extraction constants of Bu4N+Cl- and Bu4N+Br- in the CH2Cl2water two-phase system increased by a factor of 103 when 2 M K2CO3 was added.5 Once again, this behavior was ascribed to a “salting out” effect of the added K2CO3.5
Table 2. Anionic Reactivity under LL-LPTC Conditions and in Anhydrous Chlorobenzene in the Reaction of n-Octyl Methanesulfonate with Various Nucleophiles (X-) at 60 °C2
XF-
ClBrIN3CNSCNPhOPhSa
103k (M-1 s-1)b LL-PTC anhydr. (C6H5Cl-H2O) C6H5Cl
hydration number n, Q+X-‚nH2Oa 8.5 3.4 2.1 1.0 3.0 5.0 2.0 4.0 2.7
2.3 (1) 1.8 (1) 3.2 (1) 2.8 (1) 19.1 (1) 11.7 (1) 0.5 (1) 8.7 (1) 971 (1)
1890 (822) 19.7 (11) 8.1 (2.5) 3.0 (1.1) 70.4 (4) 86.7 (8) 0.75 (1.5) 650 (75) 3640 (3.7)
Q+ ) C16H33P+Bu3 or hexyl4N+. b Relative rates in parenthe-
ses. Table 3. Effect of the Specific Hydration on the Basicity of OH- in the Hofmann Elimination Reaction of Hexyl4N+OH-‚nH2O at 25 °C in PhCl-Aqueous NaOH Two-Phase Systems8 aq NaOH (%) 15 20 30 40 50 63 solid
hydration state, n, of Q+OH-‚nH2O
krel
11.0 9.0 5.0 4.0 3.5 3.3 3.0 0.0
1 7 39 1.4 × 103 1.1 × 104 2.5 × 104 5 × 104 4 × 109 (extrapolated)
Anion Reactivity as a Function of Its Specific Hydration
removal of the anion hydration sphere.
Under liquid-liquid PTC conditions the anions X-, associated with lipophilic cations Q+ (usually quaternary onium cations R4N+ or R4P+) as Q+X- ion pairs, are extracted from the aqueous to the organic phase specifically solvated by a limited number n (n ) 1-11) of water molecules (Table 1). As shown in Table 1, the n value mainly depends, within experimental error, on the nature of the anion, whereas the type of cation and the polarity of the solvent are less involved. In general, anions with high charge-to-volume ratios are found to have the greatest hydration numbers n. In addition, the electronegativity of X- is another important factor. The hydration sphere, characteristic of each anion, always reduces, more or less noticeably, the rate of “intrinsicreaction-rate-limited” PTC processes (kI , kT). The nucleophilicity of a representative series of anions (organic and inorganic) has been measured in a typical SN2 reaction in a chlorobenzene-water two-phase system in the presence of catalytic amounts of the corresponding quaternary onium salt (reaction 4).2 Under these conditions the reaction in the organic phase was found to be the rate-determining step of the overall process, the extraction of the reacting anion X- from the aqueous phase and the release of the leaving group MeSO3- being relatively fast processes. The reactivity has been compared with that measured under homogeneous conditions in anhydrous chlorobenzene (reaction 5). The results (Table 2) show that the nucleophilic reactivities of all of the anions X- increase on switching from chlorobenzene-water two-phase system (reaction 4) to homogeneous solution in anhydrous chlorobenzene (reaction 5). The enhancements, particularly relevant for F-, Cl-, CN-, and PhO-, are clearly related to the
n-C8H17OSO2Me(org) + Q+X-(org) 98
PhCl
n-C8H17X(org) + MeSO3-(org) (5) Q+ ) C16H33P+Bu3 or hexyl4N+ X- ) F-, Cl-, Br-, I-, N3-, CN-, SCN-, PhO-, PhSAs expected, the effect of the specific solvation on the reactivity (nucleophilicity, basicity) is much more pronounced in the case of anions that have high charge densities and, hence, are more hydrated. The basicity of OH- in the Hofmann elimination of hexyl4N+OH-‚nH2O (reaction 6), carried out in a chlorobenzeneaqueous (or solid) NaOH two-phase system, increases by 50000 times when the hydration number n of the anion is reduced from 11 to 3 (Table 3).8 PhCl-aq (sol) NaOH
hexyl4N+OH- 98 hexyl3N + hex-1-ene + H2O (6) The enhancement is extrapolated to be more than 109 in the hypothetical case of anhydrous hydroxide.8 The differences found in the condensed phase are comparable to those measured in reactions promoted by clusters OH-(H2O)n, in the range n ) 0-3 (5000 times) in the gas phase.9 Results confirm that, in anionpromoted reactions, the use of bulky quaternary onium salts in weakly polar non-hydrogen-bonding organic media allows for the reactivity of the gas phase (“intrinsic anion reactivity”) to be approached. It is worth noting that the largely dehydrated OHextracted from concentrated aqueous alkaline solutions
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Ind. Eng. Chem. Res., Vol. 40, No. 11, 2001
Table 4. Effect of the Specific Hydration of the F- Anion on Its Basicity in the Hofmann-like Elimination Reaction of Hexyl4N+F-‚nH2O in PhCl at 60 °C2c hydration state, n, of hexyl4N+F-‚nH2O
105k (s-1)
krel
4.6 3.2 2.4 2.0 1.7 0
0.005 0.035 1.7 9.5 38 1.2 × 105 (extrapolated)
1 7 340 1.9 × 103 7.6 × 103 2.3 × 107 (extrapolated)
Scheme 2. Schematic Representation of a SL-PTC SN2 Substitution Reaction
(50% aq NaOH or 60% aq KOH) into a low-polarity solvent such as chlorobenzene is an extremely powerful base. Results account for the dramatic effect that an increase in aqueous base concentration produces on the rate of reactions promoted by alkali hydroxides under LL-PTC conditions (PTC/OH).1,2,8,10-17 Such reactions include the generation and alkylation of carbanions,10,11 alkene isomerization,12 H/D exchange in carbon acids,13 and acid/base equilibria.14 The specific hydration also markedly affects the reactivity of the fluoride anion both as a base and as a nucleophile.2c As reported in Table 4, when the hydration number n of hexyl4N+F -‚nH2O is reduced from 4.6 to 0, the rate of the Hoffman-like elimination reaction 7 increases by more than 7 orders of magnitude. PhCl
2hexyl4N+F- 98 hexyl3N + hexyl4N+HF2- + hex-1-ene (7) Interestingly, a comparison with the data inTable 2 shows that the basicity of F- is much more affected by specific hydration than is its nucleophilicity. This clearly indicates the virtual impossibility of obtaining “naked” tetraalkylammonium fluorides (alkyl * Me) because of their instability as pure substances and in solutions of anhydrous aprotic solvents.2c Dehydrating Effect of Concentrated Aqueous Alkaline Solutions under LL-PTC Conditions From a practical point of view, the hydration sphere of the anion should be reduced or totally eliminated. In principle, this can be realized by working under SL-PTC conditions with the anionic reactant suspended as a solid phase in an anhydrous organic solution of the substrate (Scheme 2). The increase in anionic reactivity is, however, usually counteracted by at least two negative factors: (a) SL diffusion is generally rate-determining (“transferlimited” PTC process). (b) The salt generated during the process can cover the crystal surface, thus slowing or even stopping the reaction.1 Alternatively, it is possible
to work under LL-PTC conditions, provided that the water activity (aH2O) is conveniently diminished by using highly concentrated aqueous solutions of inorganic salts.18 In addition, the use of such a concentrated solution increases the catalytic activity of PTC agents that are partially soluble in water (e.g., tetrabutylammonium chloride or bromide, methyltributylammonium chloride, benzyltriethylammonium chloride) by increasing their partition in the organic phase (salting out)1; moreover, when the aqueous phase is salted, the use of organic solvents that are partially or largely miscible with water (e.g., THF, dioxane, acetonitrile, etc.) is also possible. Finally, this approach saves reactor volume and reduces the amount of wastewater. However, even saturated solutions of very soluble salts such as NaBr or NaI produce a limited aH2O drop.3 In contrast, highly concentrated aqueous alkaline solutions (50% aq NaOH, 60% aq KOH), for which the activity of the water tends to zero, prove to be very efficient systems for extracting into the organic phase the anions in largely or completely “nonhydrated” form.2d,3,18,19 The use of these concentrated alkaline solutions instead of water allows the reactivity of the homogeneous anhydrous phase (reaction 5) to be obtained. The enhancements in reactivity compared with that of the classic LL-PTC conditions (chlorobenzeneaq MX two-phase systems) range between 1.1 and 75 times for I- and PhO-, respectively (Table 2). It is worth noting that such behavior is only peculiar to concentrated alkaline solutions. At lower base concentrations, the anion hydration progressively increases with increasing water activity and even 30% aq NaOH solutions no longer have a dehydrating effect.3,19 The concentration of the aqueous alkaline solution strongly affects the C-/O- alkylation selectivity of enolates. For example, the C-/O- alkylation ratio for the PTC methylation of deoxybenzoin with dimethyl sulfate progressively decreases as the base concentration decreases from 50 to 20% aq NaOH.1c,13a This trend was attributed to a higher increase in the hydration state of the more electronegative oxygen atom with respect to the carbon center of the ambident ion pair as a function of the water amount in the system.1c,13a As a result, alkylation at the less-hydrated center, the carbon, becomes the preferred process.1c,13a,15 The use of concentrated aqueous alkaline solutions (50% NaOH, 60% KOH) combines two important and advantageous effects for the formation and reactions of carbanions, oxanions, and azanions under PTC/OH conditions: (i) It allows for the generation of anions even from very weak organic acids (up to pKa ) 38), making the PTC/OH technique a valid and advantageous alternative to the classic procedures that involve expensive solvents, rigorously anhydrous systems, and sometime dangerous bases such as metal hydrides or organometallic reagents, particularly in industrial processes.1,2,8,15-17 (ii) It secures the anhydricity of the organic phase, avoiding the negative effect on the anion reactivity by water produced in the deprotonation step.1-3,8,15,19 On the other hand, under PTC/OH conditions in the presence of less concentrated inorganic bases ( 1 are even better extracted than Cl-, with enhancements of the selectivity coefficients by up to 7.5 times (for the benzoate anion). In contrast, anions with selectivity coefficients 1 are those most favored by concentrated alkaline solutions (50% aq NaOH) because the higher partition of the reacting X- in the organic phase is combined in this case with enhanced anion activation. On the other hand, the dramatic increase in reactivity found under these conditions for the anions with selectivity coefficients
