Enforced Hydrophobic Interactions and Hydrogen Bonding in the

Chapter 21

Enforced Hydrophobic Interactions and Hydrogen Bonding in the Acceleration of Diels—Alder Reactions in Water 1

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on February 2, 2016 | http://pubs.acs.org Publication Date: September 29, 1994 | doi: 10.1021/bk-1994-0568.ch021

Wilfried Blokzyl

and Jan B . F. N . Engberts

Department of Organic and Molecular Inorganic Chemistry, University or Groningen, Nyenborgh 4, 9747 A G Groningen, The Netherlands

Following pioneering work of Breslow, Grieco and others, we find that intermolecular Diels- Alder (DA) reactions of cyclopentadiene with alkyl vinyl ketones and 5-substituted-l,4 naphthoquinones as well as intramolecular D A reactions of N-furfuryl-N-alkylacrylamides are greatly accelerated in water as compared with traditional organic solvents. Iso baric activation parameters in combination with thermodynamic quantities for transfer of reactants and activated complex from alcohols and alcohol-water mixtures to water indicate, that the decrease of the hydrophobic surface area of the reactants during the activation process ("enforced hydrophobic interactions") is an important factor determining the rate enhancement in water. A second factor involves hydrogen-bond stabilization of the polarized activated complex. Aggregation or stacking of the reactants do not play a role at the concentrations used for the kinetic measurements. In alcohol-water mixtures the rate accelerations are confined to the highly water-rich solvent composition range and result from favorable changes in both Δ Η and Δ S . #

ө

#

ө

For a large variety of Diels-Alder (DA) reactions, both rate constants and stereospecificities are little or only moderately sensitive to changes in the nature of the reaction medium (7). However, in 1980 Breslow et al.(2) showed that, quite surprisingly at that time, D A reactions are dramatically accelerated in aqueous solution. Ever since, similar curious rate effects have been found for many other organic reactions including Claisen rearrangements (J), benzoin condensations (4) and aldol reactions of silyl enol ethers (5). A common aspect of these reactions is that the reactants are relatively apolar species. Particularly Grieco et al.(6) have shown that the remarkable rate enhancements in water are not just curiosities but that 1

Current address: Unilever Research Laboratories, P.O. Box 114, 3130 AC Vlaardingen, The Netherlands

0097-6156/94/0568-0303$08.00/0 © 1994 American Chemical Society

In Structure and Reactivity in Aqueous Solution; Cramer, Christopher J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.


304

STRUCTURE AND REACTIVITY IN AQUEOUS SOLUTION

water can be a highly useful solvent in synthetic organic chemistry. Recently, the first extensive review of organic reactions in aqueous media has appeared (7). Sever al explanations have been presented to account for the high rate constants of D A processes in water. These include micellar-like catalysis (8), effects due to the high cohesive density of water (9), internal pressure (10), solvophobicity (11) and enhanced hydrogen bonding to the carbonyl function in the activated complex (12). Breslow (13) proposed that "hydrophobic packing" of diene and dienophile is the most likely explanation, largely based upon kinetic studies of D A reactions in water in the presence of "salting-in" and "salting-out" materials. Apart from aqueous solvent effects, D A reactions can be accelerated by Lewis-acid catalysis and catalytic antibodies (14) and by increased external pressure. Finally, we note that D A reactions are often speeded up in "organized aqueous media", such as microemulsions (15), micellar systems (16) and clay emulsions (17). These rate effects have been attributed to cage effects, pre-orientation of the reactants, microviscosity effects and local concentration effects. Interestingly, D A processes can also be quite fast in heterogeneous aqueous media (7). In an endeavor to obtain a proper understanding of the reasons for the rate acceleration of D A reactions in water, we have performed a detailed kinetic study of the intermolecular D A reactions of cyclopentadiene (1) with alkyl vinyl ketones (2a,b) and 5-substituted-1,4-naphthoquinones (3a-c) in water, in alcohols and alcohol-water mixtures and in a series of organic solvents (18,19) (Scheme 1). Furthermore we have examined solvent effects on the intramolecular D A reaction of N-furfuryl-N-alkylacrylamides (18,20). Effects due to the hydrogen-bond acceptor capability of the dienophile have been probed via a comparison of the rates of the D A reaction of 1 with methyl vinyl ketone (2a) and methyl vinyl sulfone (4) (21). It will be shown that the rate acceleration of the D A reactions in water is governed by the decrease of the hydrophobic surface area of the reactants during the activation process ("enforced hydrophobic interactions"). A second factor involves hydrogenbonding stabilization of the polarizable activated complex.

Kinetic Solvent Effects on Intermolecular D A Reactions in Water The rate constants for the intermolecular D A reactions studied (Scheme 1) are spectacularly enhanced in water. For example, the second-order rate constant for the reaction of 1 with 3a is increased by a factor of 7600 going from n-hexane to water. For a series of 17 organic solvents, the Gibbs energy of activation for the reaction of 1 with 3c shows a trend with the solvent polarity as expressed in the DimrothReichardt Ef(30) value (Figure 1), but the reaction in water is much faster than expected on the basis of this trend. A similar result is obtained if A G® for the same reaction is plotted against the acceptor numbers of the solvents following a procedure advanced by Desimoni et al.(2J). The following discussion will be focused on a quantitative analysis of rate constants and isobaric activation parameters of the D A reactions in water, in some monohydric alcohols and in binary mixtures of water with these alcohols. Relevant data are presented in Table I. It is clear that the substantial rate accelerations going from the alcohols to water are reflected in a more favorable magnitude of both Δ * Η and -TA S®. Second-order rate constants for the D A reaction of 1 with 3a in EtOH-H 0, n-PrOH-H 0, and t-BuOH-H 0 (Figure 2) #

θ

#

2

2

2


21.

Acceleration ofDiek-Alder Reactions in Water 305

B L O K Z U L & ENGBERTS


0

3 b R = 0H #

3c. R = 0 C H

3

Scheme 1 A*G*'.kJ.mol

95

μ

75 Y

65 * 25

« 30

« 35

' 40

» « 45 50 E,(30)

' 55

« 60

1

65

Figure 1. Gibbs energy of activation for the Diels-Alder reaction of 1 with 3c in nhexane (1), tetrachloromethane (2), benzene (3), 1,4-dioxane (4), T H F (5), chloroform (6), dichloromethane (7), acetone (8), D M S O (9), acetonitrile (10), 2propanol (11), ethanol (12), N-methylacetamide (13), N-methylformamide (14), methanol (15), glycol (16), trifluoroethanol (17) and water (18) as a function of Er(30) at 25°C. In Structure and Reactivity in Aqueous Solution; Cramer, Christopher J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

306

S T R U C T U R E A N D REACTIVITY IN A Q U E O U S S O L U T I O N


Table I. Second-order Rate Constants and Isobaric Activation Parameters for the Diels-Alder Reactions of Cyclopentadiene (1) with Dienophiles 2a, 2b, and 3a-c in Aqueous Solutions and Organic Solvents, at 25°C

D

a

Solvent

k 3

ΔΌ

2

1

dm m o l s

Methanol

45,.1(0. 7)

45..3(0. 7)

39..4(0. 7)

40..9(0. 7)

80..35

45.6x10

3

80..68

40.5χ10

3

80,.97

29.5χ10

3

81,.75

20.8χ10

3

82 .63

Water+CTAB

C

1

90..37

3

Water+CTAB

kJ mol

90..50

51.9x10

B

1

3

Water

Water+SDS

kJ mol

-TA'S'

90, 46

0.912χ10

C

1

Θ

3

1-Propanol

b

#

Δ Η

3

0.868χ10·

Water+SDS

90 .82

45 .8(0..5)

45 .0(0,.6)

48.9χ10

3

80 .50

41 .5(0,.6)

39 .0(0,.6)

1-Propanol

17.6χ10

3

83 .05

42 .9(0,.6)

40 .1(0,.6)

Water

4.28

69 .42

36 .6(0. 4)

32 .8(0,.5)

81,.54

44,.2(0.,5)

37,.3(0,.6)

69 .39

44,.2(0..8)

25,.2(0. 8)

83 .44

43,.3(1. .0)

40 .2(1. 0)

68,.91

40 .5(0. 7)

28,.4(0. 7)

1-Propanol Water

1-Propanol Water

β

kJ m o l

1

0.883xl0"

Ethanol

Θ

0.762χ10

32.2χ10"

3

3

4.33

1-Propanol

14.9χ10

Water

5.26

b

3

Dienophile. 50 mmol in 1 kg of water.

c

100 mmol in 1 kg of water.



21.

BLOKZIJL & E N G B E R T S

Acceleration of Diels-Alder Reactions in Water 307

Figure 2. Second-order rate constants for the Diels-Alder reaction of 1 with 3a in mixed aqueous solutions as a function of the mole fraction of water at 25°C.; · , ethanol; • , 1-propanol; A, 2-methyl-2-propanol.


308

S T R U C T U R E A N D REACTIVITY IN A Q U E O U S S O L U T I O N

show that the large rate enhancements going to water are confined to the water-rich solvent composition range. This type of behavior is general for all D A reactions examined in this study. We note that for the reaction of 1 with 3a-c even a slight increase of k is found upon the addition of small amounts of n-PrOH and t-BuOH to water. This remarkable effect was not observed for the D A reactions of 1 with 2a-b. The solvent has also a marked effect on the endo/exo product ratios for the reactions of 1 with 2a and 2b (Figure 3). Again the greatest solvent-dependence is found in the water-rich region. In mixed aqueous solvent systems with high mole fractions of water (X(H 0) = 0.95-1.00), the effect of the cosolvent on the secondorder rate constant for the D A reactions is modest (data are given in ref. (22)). Since the cosolvent is not aggregated in this dilute region, we conclude that the sum of the Gibbs energies for the pairwise interactions of the cosolvent with diene and dienophile almost equals the pairwise interaction of the cosolvent with the activated complex. Interestingly, A H® and A S® undergo large changes upon addition of e.g. small amounts of 1-PrOH (Figure 4). However, these changes are largely compensating, leading to modest changes in A'G®. For the reaction of 1 with 3c, the rate-accelerating effect in water relative to pure 1-PrOH is almost entirely entropie in origin, whereas the rate accelerating effect at X ( H 0 ) = 0.9 (i.e.. at 10 mol % of 1-PrOH) is overwhelmingly caused by a favorable enthalpy change (ÔA*H = 22 kJ.mol vs. - MeCN > EtOH > C F C H O H > -(CF ) CHOH > H 0, consistent with the idea that enforced hydrophobic interactions and hydrogen-bond stabilization of the A C both contribute to the rate acceleration in aqueous media. 3

2

3

2

2

Comparison of Methyl Vinyl Ketone and Methyl Vinyl Sulfone as the Dienophile The proposed explanation for the high rates of D A reactions in aqueous solutions implies that the kinetic solvent effect will respond to changes in overall hydrophobicity of the IS and hydrogen-bond capability of the A C . This is borne out in practice by a comparison of kinetic solvent effects on the reaction of 1 with methyl vinyl keton (2a) and methyl vinyl sulfone (4) (27). Reaction rates for the reaction of 1 with 4 were determined in M e C N , EtOH, 1-PrOH, C F C H O H , (CF )2CHOH and water. It was found that the rate enhancement going from MeCN to water amounts to 71x for 4 as compared with 250x for 2a. Combination of Gibbs energies of activation with Gibbs energies of transfer of 4 from C H C N to water led to the somewhat unexpected result that 4 is less hydrophobic than 2a. The presence of two oxygen hydrogen-bond acceptor sites in the sulfone compared to one in the ketone may account for this result. It is obvious that the rate acceleration for a particular D A process in aqueous solution depends on a quite specific way on the nature of the diene and dienophile as far as hydrophobicity and hydrogen-bonding capability is concerned. 3

3

3


2

21.

BLOKZUL & ENGBERTS

Acceleration ofDkh-AMer Reactions in Water 315

Intramolecular D A Reactions in Water The intramolecular version of the D A reaction is over twenty years younger than its bimolecular counterpart. The first example was reported by Alder et al.(28). The reaction is of great utility in natural product synthesis (29). Because of its intramolecular nature, "entropie assistance" often leads to Gibbs energies of activation which are 22-30 kJ.mol" lower than those for analogous bimolecular D A reactions. We have found that the intramolecular D A (IMDA) reaction of N-furfuryl-Nmethylmaleamic acid (5a; Scheme 2) is also greatly accelerated in water (18,20). Some further examples are listed in Table II (20,22). The rate enhancements in water are comparable to those for intermolecular D A processes in aqueous solution. *H-NMR studies (20) indicate that the high rate constants for I M D A reactions cannot be attributed to enhanced concentrations of the s-cis conformation in water. Apparently, the high rate of I M D A reactions in water can be rationalized by similar considerations as outlined above for the intermolecular D A reactions. A detailed account of I M D A reactions in water will be given elsewhere (20).


1

Conclusions It appears that several previous explanations for the large rate enhancements of D A reactions in aqueous solution are ambiguous or even fallacious. For example, the effect cannot be rationalized in terms of the internal pressure since the internal pressure of water is small instead of large (1,30). Furthermore, micellar effects are also not operative since micelles retard instead of accelerate D A reactions as compared with the reaction in water (Table I). The present results indicate that two factors dominate the rate acceleration in water: (1) enforced hydrophobic interactions during the activation process and (2) hydrogen-bond stabilization of the polarizable activated complex. A quantitative assessment of the relative contributions of both

R

Ο 5a, R = methyl 5b,R = ethyl 5ç, R = n-propyl Sci R = n-octyl Scheme 2


316

STRUCTURE AND REACTIVITY IN AQUEOUS SOLUTION

Table II. Rate Constants and Gibbs Energies of Activation for the I M D A Reactions of 5a-d in a Series of Organic Solvents and in Water at 25°C

Compound

Solvent

Rate Constant s


1

5a 5a 5a 5a 5a 5a 5a 5a 5b 5b 5b 5c 5c 5c 5d 5d 5d

Ethanol 1-Propanol Hexane 1,4-Dioxane Dichloromethane Acetonitrile Trifluoroethanol Water Ethanol 1-Propanol Water Ethanol 1-Propanol Water Ethanol 1-Propanol Water

3.09x1ο2.90xl0 1.63xl0~ 4.93xl0 2.36xl0" 9.27xl02.82xl0' 2.50xl0" 4.10xl03.65xl0" 2.94xl0

4

4

4

5

5

5

3

2

4

4

2

4.77X10-

4

4.37X10-

4

1.80xl04.85xl0' 4.36xl0 1.40x10

2

4

4

2

#

A G® kJ m o l

1

93.1 93.2 94.6 97.6 99.4 96.0 87.6 82.0 92.4 92.6 81.8 92.0 92.2 83.0 91.9 92.2 83.6

effects is difficult and will depend, inter alia, on the reference solvent employed for characterizing the hydrophobicity of diene and dienophile. Our experimental results are fully consistent with the elegant computer simulations performed by Jorgensen et al.(72,27). Literature Cited (1) (2) (3) (4) (5) (6) (7) (8)

Reichardt, C. Solvents and Solvent Effects in Organic Chemistry; VCH: Cambridge, UK; 1990. Rideout, D.C.; Breslow, R.J.Am.Chem.Soc. 1980, 102, 7816. Grieco, P.A.; Brandes, E.B.; McCann, S.; Clark,J.D.J.Org.Chem.1989, 54, 5849. Kool, E.T.; Breslow, R.J.Am.Chem.Soc.1988, 110, 1596. Lubineau, Α.; Meyer, E. Tetrahedron 1988, 44, 6065. Grieco, P.A. Aldrichim.Acta 1991, 24, 59. L i , C-J. Chem.Rev. 1993, 93, 2023. Grieco, P.Α.; Yoshida, K.; Garner, P.J.Org.Chem.,1983, 48, 3137. In Structure and Reactivity in Aqueous Solution; Cramer, Christopher J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

21. BLOKZUL & ENGBERTS

(9) (10) (11) (12)


(13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30)

Acceleration of Dkh-AMer Reactions in Water 317

Grieco, P.Α.; Larsen, S.D.; Fobare, W.F. Tetrahedron Lett. 1986, 27, 1975. Lubineau, Α.; Queneau, Y. J.Org.Chem. 1987, 52, 1001. Sangwan, N.K.; Schneider, H-J. J.Chem.Soc. Perkin Trans.2 1989, 1223. Blake, J.F.; Jorgensen, W.L. J.Am.Chem.Soc. 1991, 113, 7430. Breslow, R. Acc.Chem.Res. 1991, 24, 159. Hilvert. D.; Hill, K.W.; Nared, K.D.; Auditor, M.T.M. J.Am.Chem.Soc. 1989, 111, 9262. Ramamurthy, V. Tetrahedron 1986, 42, 5753. Sakellarou-Fargues, R.; Maurette, M-T.; Oliveros, E.; Riviere, M . ; Lattes, A. J.Photochem. 1982, 18, 101. Lazlo, P.; Lucchetti, J. TetrahedronLett.1984, 25, 2147. Blokzijl, W.; Blandamer, M.J.; Engberts, J.B.F.N. J.Am. Chem.Soc. 1991, 113, 4241. Blokzijl, W.; Engberts, J.B.F.N. J.Am.Chem.Soc. 1992, 114, 5440. Blokzijl, W.; Engberts, J.B.F.N. To be published. Otto, S.; Blokzijl, W.; Engberts, J.B.F.N. To be published. Blokzijl, W. Ph.D. Thesis, University of Groningen, 1991. Desimoni, G.; Faita G.; Righetti, P.P.; Toma, L. Tetrahedron 1990, 46, 7951. Jung, M.E.; Gervay, J. J.Am.Chem.Soc. 1991, 113, 224. Blokzijl, W.; Engberts, J.B.F.N. Angew.Chem., Int.Ed. Engl. 1993, 32, 1545. Ben-Naim, A. Hydrophobic Interactions, Plenum: New York, N.Y., 1980. Jorgensen, W.L.; Blake, J.F.; Lim, D.; Severance, D.J. J.Chem.Soc., Far.Trans. 1994, in press. Alder, K.; Schumacher, M . Fortschr. Chem. Org.Naturstoffe 1953, 10, 66. For a recent review, see: Roush, W.R. Adv.Cycloaddit. 1990, 2, 91. Dack, M.J.R. Chem.Soc.Rev. 1975, 4, 211.

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1994


Enforced Hydrophobic Interactions and Hydrogen Bonding in the

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