Intramolecular nucleophilic addition of phenolate oxygen to double

yield of 7c or 8c may be obtained at higher or lower pH, re- spectively. IonizatiOn Cotstants. The ionization constants for the carboxylic acid (Kal) ...
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6505

J . Am. Chem. SOC.1988,110, 6505-6514

Intramolecular Nucleophilic Addition of Phenolate Oxygen to Double Bonds Activated by Carboxyl and Carboxylate Groups. Relative Reactivity, Stereochemistry, and Mechanism Tina L. Amyes and Anthony J. Kirby* Contribution from the University Chemical Laboratory, Lensfield Road, Cambridge CB2 1E W,UK. Received February 16, 1988

Abstract: The cyclization reactions of substituted 4-methyl-4-(2-hydroxyphenyl)pent-2-enoicacid derivatives (7) in water

-

involve intramolecular nucleophilic attack of phenolate oxygen on the activated double bond. Activation by COO- and COOH groups gives rate enhancements over a hydrogen substituent of 4000 and IO8,respectively, for the unsubstituted acid. Both mono- and dianion reactions are general-acid-catalyzed by protonated amines (a 0.2). The stereochemistry of these latter reactions (syn addition of phenol 0 and general-acid H) is in remarkable contrast with the trans addition observed for the water-catalyzed reaction, and the (primary) solvent deuterium isotope effects (less than 2 for buffer acids, compared with - 5 for water) are also very different. The most likely mechanisms involve rate-determining protonation of mono- or dianions of carboxylic acid enolates, thus formally, reverse (ElcB), reactions.

We recently described the rapid cyclization of a series of phenol olefins, e.g., 1; involving intramolecular nucleophilic addition of phenolate oxygen to the unactivated double bond of a monoalkyl ethylene.' In this situation, with cyclization favored by the release 0-

H

Scheme I

HI m

?ACH3

H-A

' A-

2

1

of ground-state strain, the alkene clearly prefers to act as an electrophile. Nucleophilic addition requires the presence of a preasswiated general acid, but proton transfer is not far advanced in the transition state, though of course it plays an essential role in avoiding the formation of a primary alkyl carbanion in water. These results define the basic requirements for the addition of an oxygen nucleophile like water to an unactivated double bond,' a reaction catalyzed by a number of interesting enzymes. The hydration catalyzed by fumarase (EC 4.2.1.2) (3 4)* involves a double bond activated by a carboxylate or carboxyl group. Several mechanisms have been proposed. Early work with halofumarate substrates led to the suggestion of a pathway involving a carbocation? and this was supported by isotope-exchange results! Rose,5 however, considering the reverse reaction, argued that the relative timing of C-H and C-OH bond cleavage is not easy to assess from such studies and that concerted and carbanion mechanisms could not be excluded. More recent work by Lowe et aL6 provides kinetic evidence for a concerted pathway. But a comprehensive isotope effect study led Blanchard and Cleland' to favor the carbanion mechanism (Scheme I). Independent support for a carbanion intermediate comes from the observations that 6 is a tight-binding competitive inhibitor of the enzyme.

Scheme I raises some interesting questions, particularly concerning the viability of the carbanion intermediate (5 is formally a carboxylic acid dianion) in a protic medium. If such an intermediate has a significant lifetime in water, it should be generated by an intramolecular cyclization reaction (cf. 1 2). So we have prepared and studied the cyclization (7 8) of a series of substituted 4-methyl-4-(2-hydroxyphenyl)pent-2-enoicacid derivatives.

--

CO?H

X

X ?a 7b

?e

88 X = H 8b X Br 8~ X = NO,

K.H

X = Br X I NO, CO, Et I

OH

6

(1) Evans, C. M.; Kirby, A. J. J . Chem. Soc., Perkin Trans. 2 1984, 1259. (2) Hill, R. L.; Teipel, J. W. Enzymes, 3rd ed. 1971, 5. (3) (a) Teipel, J. W.; Hass, G. M.; Hill, R. L. J . Biol. Chem. 1968, 243, 5684. (b) Nigh, W. G.; Richards, J. H. J . Am. Chem. SOC.1969.91, 5847. (4) Hansen, J. N.; Dinovo, E.C.; Boyer, P. D. J . Biol. Chem. 1969, 244, 6270. ( 5 ) Rose, I. A. Enzymes, 3rd ed. 1970, 2. ( 6 ) Jones, V. T.; Lowe, G.; Potter, B. V. L. Eur. J . Biochem. 1980, 108, 433. (7) Blanchard, J. S.; Cleland, W. W. Biochemisfry 1980, 19, 4506. (8) Porter, D. J. T.; Bright, H. J . J . Biol. Chem. 1980, 255, 4772.

0002-7863/88/1510-6505%01.50/0

9

Experimental Section Materials. Diisopropylamine was distilled from and stored over cal-

cium hydride. Triethyl phosphonoacetate was from Lancaster Synthesis. Diisobutylaluminum hydride (DIBAL) was from Aldrich. Dichloromethane was distilled from phosphorus pentoxide. Tetrahydrofuran (THF) was predried by distillation from lithium aluminum hydride, stored over sodium wire, and redistilled from sodium-benzophenone. Acetonitrile was distilled from phosphorus pentoxide. Inorganic buffer 0 - 1988 American Chemical Societv

6506 J . Am. Chem. SOC.,Vol. 110, No. 19, 1988 salts were of AnalaR grade and were used without further purification, apart from drying in vacuo where necessary. Piperidine was distilled from calcium hydride, and ethanolamine and propanolamine were distilled before use. Other amines were obtained as, or converted to, the hydrochlorides and then recrystallized. Distilled water was distilled twice more from all-glass apparatus. Unless stated otherwise, all other reagents were of analytical grade. Synthesis. 'H N M R spectra were recorded at 60 MHz on a Varian EM 360 spectrometer, at 90 MHz on a Varian EM 390 spectrometer, at 80 MHz on a Bruker WP 80 spectrometer, and at 250 MHz on a Bruker WM 250 spectrometer. Chemical shifts are reported as 6 (ppm) downfield of an internal tetramethylsilane standard at 0 ppm. Highresolution mass spectra were recorded on an AEI MS30 mass spectrometer. Infra-red spectra were recorded on a Perkin-Elmer 297 spectrophotometer. Ultraviolet spectra were recorded on a Gilford 2600 spectrophotometer. Melting points were determined with a Kofler hot stage apparatus and are uncorrected. Column chromatography was carried out using Merck Kieselgel 60 (70-230 mesh). Chromatographic solvents were distilled before use. 3,3-Dimethyl-2(3H)-bnzofuranone (10) was prepared by lactonization of o-hydroxyphenylacetic acid followed by methylation with methyl iodide using a published procedure9 to give the dimethylated lactone as an oil: bp 63 OC (0.4 mmHg) (lit.lo bp 101-102 OC (2 mmHg); IR (liquid film) 1800 cm-' (C=O); 'H N M R (60 MHz, CDCI,) 6 7.1-6.6 (4 H, m, Ar), 1.47 (6 H, s, CH,); MS (found Mt 162.0682, CIOH1002 requires M 162.0681), m / z 162 (50, M+), 134 (91, M - CO), 119 (88), 91 (100). 2,3-Dihydro-3,3-dimethyl-2-henzofuranol (11). DIBAL (40 mL of a 1 M solution in heptane, 40 mmol) was added to a stirred solution of the lactone 10 (5 g, 31 mmol) in dry dichloromethane (80 mL) under nitrogen at -78 "C. Stirring was continued for l h, and the mixture was treated with hydrochloric acid to dissolve the aluminum salts formed. The mixture was extracted with dichloromethane (3 X 100 mL), dried (Na2S04), and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (200 g) eluting with 2/11 ethyl acetate/hexane to give the lactol 11 (4.2 g, 83%) as needles: mp 56-58 OC; IR (CCI4) 3600 cm-l (OH); ' H NMR (60 MHz, CDCI,) 67.1-6.5(4H,m,Ar),5.4(1 H , d , J = 6 H z , C H ) , 3 , I ( I H , d , J = 6 Hz, OH), 1.33 (3 H, s, CH,), 1.27 (3 H, s, CH,); "C N M R (62.9 MHz, CDCI,) 6 156.2, 135.4, 128.1, 122.6, 121.4, 110.0 (Ar), 108.5 (OCO), 45.2 (C), 27.7 (CH,), 20.2 (CH,); MS (found M+ 164.0834, CloH1202requires M 164.0837), m / z 164 (46, M+), 135 (100). Anal. Calcd for CIOHI2O2:C, 73.1; H, 7.35. Found: C, 73.0; H, 7.30. Ethyl 2,3-Dihydro-3,3-dimethyl-2-benzofuranacetate (12a). Triethyl phosphonoacetate (5.38 g, 24 mmol) in dry T H F (25 mL) was added dropwise to a stirred solution of oil-free sodium hydride (0.96 g of a 60% dispersion, 24 mmol) in dry T H F ( I O mL) under nitrogen at 0 OC. The mixture was stirred for 10 min at room temperature, after which the lactol 11 (1.5 g, 9 mmol) in dry T H F ( I O mL) was added. The mixture was stirred at room temperature for 20 h and saturated ammonium chloride (20 mL) added. The T H F was removed under reduced pressure and the residue extracted with ether (3 X 50 mL). The combined extracts were washed with water (50 mL), dried (Na,SO,), and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (200 g) eluting with 2/11 ethyl acetate/hexane to give the ester 12a (2 g, 93%) as an oil: IR (liquid film) 1740 cm-' (C=O); 'H N M R (250 MHz, CDCI,) 6 7.14-6.77 (4 H, m, Ar), 4.73 (1 H, dd, J = 4.4, 9.3 Hz, OCH), 4.23 (2 H, q, J = 7 Hz, CH,CH,), 2.75 (1 H,dd, J = 9.3, 15.7 Hz, CHAHB), 2.61 (1 H,dd, J = 4.4, 15.7 Hz, CHAHB), 1.36 (3 H, S , CH,), 1.30 (3 H, t, J = 7 Hz, CHZCH,), 1.14 (3 H, s, CH,); 13C N M R (62.9 MHz, CDCI,) 6 171.0 (C=O), 157.8, 136.7, 128.0, 122.3, 120.8, 109.9 (Ar), 88.4 (OCH), 60.8 (CH,CH,), 43.7 (C), 35.6 (CH,CO,Et), 26.8 (CH,), 23.5 (CH,), 14.2 (CH2CH3); MS (found Mt 234.1254, C14HlBOJ requires M 234.1256), m/z 234 (46, Mt), 219 (36, M - Me), 145 (100).

Ethyl 5-Bromo-2,3-dihydro-3,3-dimethyl-2-benzofuranacetate (12b). Bromine (13 mL of a 0.5 M solution in CCI,, 6.5 mmol) was added to a stirred solution of the ester 12a (1.53 g, 6.5 mmol) in CCI, ( I O mL) in an open flask at 0 OC. The mixture was stirred at room temperature for 4 h and the CC14 removed under reduced pressure. The residue was taken up into dichloromethane (50 mL), washed with sodium thiosulfate solution (20 mL) and with brine (20 mL), dried (MgS04), and evaporated under reduced pressure. The residue was distilled to give the ester 12b (1.95 g, 95%) as an oil: bp 185 OC (0.1 mmHg); IR (liquid film) 1730 cm-' (C=O); 'H N M R (250 MHz, CDCI,) 6 7.2-7.14 (2 H, m, Ar), 6.65 ( I H, d, J = 8.3 Hz, Ar), 4.73 (1 H, dd, J = 4.4, 9.2 Hz, OCH), 4.20 (2 H, q, J = 7 Hz, CH2CH,), 2.72 (1 H, dd, J = 9.2, 15.8 (9) Elix, J. A.; Ferguson, B. A. Aust. J . Chem. 1973,26, 1079. (10) Gripenberg, J.; Hase, T. Actn Chem. Scand. 1966, 20, 1561

Amyes and Kirby Hz, CHAHB), 2.61 (1 H, dd, J = 4.4, 15.8 Hz, CHACHB), 1.33 (3 H, CHJ, 1.28 (3 H, t, J = 7 Hz, CH,CH,), 1.1 1 (3 H, S, CH3); I3C NMR (62.9 MHz, CDCI,) 6 170.7 (C=O), 156.9, 139.1, 125.5, 112.6, 111.6 (Ar), 88.9 (OCH), 60.9 (CH,CH,), 44.0 (C), 35.4 (CH,CO,Et), 26.6 (CH,), 23.3 (CH,), 14.3 (CH2CH3); MS (found M+ 312.0374, C14HI7BrO, requires M 312.0361), m/z 312 (44, M'), 297 (25, M -Me), 225 (IOO), 223 (87).

S,

Ethyl 2,3-Dihydro-3,3-dimethyl-5-nitro-2-benzofuranacetate (12c). 12a (5 g, 21.4 mmol) and silver nitrate (3.99 g, 23.5 mmol) were stirred together in dry acetonitrile (30 mL) at 0 OC. Acetyl chloride (1.67 mL, 23.5 mmol) in dry acetonitrile (20 mL) was added dropwise, followed by more dry acetonitrile (20 mL). The mixture was stirred at 0 OC for 0.5 h and then at room temperature for 0.5 h. Water (10 mL) was added and the mixture extracted with dichloromethane (3 X 200 mL). The combined extracts were dried (MgS0,) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (300 g) eluting with 2/11 ethyl acetate/hexane to give the ester 12c (4.1 1 g, 69%) as a yellow solid: mp 89-91 OC; IR (CC1.J 1740 (C=O), 1530 (NO,), 1350 cm-' (NO,); IH NMR (250 MHz, CDCI,) 6 8.09 (1 H, dd, J = 2.4, 8.8 Hz, Ar), 7.97 (1 H, d, J = 2.4 Hz, Ar), 6.82 (1 H, d, J = 8.8 Hz, Ar), 4.91 (1 H, dd, J = 4.5, 9.2 Hz, OCH), 4.23 (2 H, q, J = 7.1 Hz, CH,CH,), 2.76 (1 H, dd, J = 9.2, 16 Hz, CHAH,), 2.65 (1 H, dd, J = 4.5, 16 Hz, CHAHB), 1.42 (3 H, S , CH,), 1.30 (3 H, t, J = 7.1 Hz, CH2CH3), 1.19 (3 H, s, CH,); I3C N M R (62.9 MHz, CDCI,) 6 170.2 (C=O), 163.1, 142.5, 138.2, 125.7, 119.0, 109.9 (Ar), 90.5 (OCH), 61.6 (CH,CH,), 43.5 (C), 35.4 (CH,CO,Et), 26.8 (CH,), 23.5 (CH,), 14.1 (CH2CH3);MS (found Mt 279.1086, CI4Hl7NOS requires M 279.1107), m / z 279 (18, M+), 264 (24, M - Me), 190 (100). Anal. Calcd for Cl,H17NOS: C, 60.2; H, 6.15; N, 5.0. Found: C, 60.0; H, 6.35; N, 4.80. 2,3-Dihydro-3,3-dimethyl-2-benzofuranacetic Acid (Sa). Ester 12a (0.55 g, 2.4 mmol), potassium hydroxide (0.44 g, 7.9 mmol), water (30 mL), and T H F (30 mL) were heated under reflux for 21 h. The T H F was removed under pressure and the mixture acidified with concentrated hydrochloric acid. The mixture was extracted with ether (3 X 20 mL) and the combined extracts were dried (MgSO,) and evaporated under reduced pressure. The residue was recrystallized from ether/hexane to give the acid Sa (0.37 g, 76%) as prisms: mp 106 OC; IR (CCI,) 3500-2500 (OH), 1710 cm-I (C=O); 'H NMR (250 MHz, CDCI,) 6 7.16-6.80 (4 H, m, Ar), 4.73 (1 H, dd, J = 4.1, 9.4 Hz, OCH), 2.79 (1 H, dd, J = 9.4, 16 Hz, CHACHB), 2.69 (1 H, dd, J = 4.1, 16 Hz, CHACHB), 1.38 (3 H, S, CH,); I3C N M R (62.9 MHz, CDCI,) 6 176.1 ( ( 2 4 ) . 157.6, 136.4, 128.1, 122.3, 121.0, 110.0 (Ar), 88.0 (OCH), 43.8 (C), 35.2 (CH,), 26.9 (CH,), 23.4 (CH,); MS (found M+ 206.0940, C12H1403 requires M 206.0943), m/z 206 (23, M+), 191 (24, M - Me), 145 (100). Anal. Calcd for C12Hl,0,: C, 69.9; H, 6.85. Found: C , 69.6; H , 6.80. Prepared in a similar fashion were the following. 5-Bromo-2,3-dihydro-3,3-dimethyl-2-benzofuranacetic acid (Sh): prisms; mp 125-1 26 "C; IR (CHCI,) 3500-2500 (OH), 1710 cm-' (C=O); 'H N M R (250 MHz, CDCI,) 6 7.23-7.16 (2 H, m, Ar), 6.68 (1 H, d, J = 8.4 Hz, Ar), 4.74 (1 H, dd, J = 4.2, 9.4 Hz, OCH), 2.77 (1 H, dd, J = 9.4, 16 Hz, CHAHB), 2.67 (1 H, dd, J = 4.2, 16 Hz, CHAHB), 1.36 (3 H, S , CH?), 1.15 (3 H, s, CH,); ',C NMR (62.9 MHz, CDCI,) 6 175.6 (C=O), 156.8, 139.0, 131.0, 125.6, 112.9, 111.7 (Ar), 88.6 (OCH),44.1 (C), 35.1 (CHI), 26.8 (CH,), 23.3 (CH,); MS (found MC284.0040, Cl2H1,BrO, requires M 284.0048), m / z 284 (75, M'), 269 (50, M - Me), 223 (100). Anal. Calcd for C12H13Br03:C, 50.5; H, 4.60. Found: C, 50.6; H, 4.50. 2,3-Dihydro-3,3-dimethyl-5-nitro-2-benzofuranacetic acid (Sc): yellow needles; mp 199-200 OC; IR (CHCI,) 1710 cm-' ( C 4 ) ; 'H N M R (250 MHz, Me2SO-d6) 6 8.14-8.06 (2 H, m, Ar), 6.98 (1 H, d, J = 8.8 Hz, Ar), 4.83 (1 H, dd, J = 3.5, 9.9 Hz. OCH), 2.86 (1 H, dd, J = 3.5, 16.3 Hz, CHAHB), 2.61 (1 H, dd, J = 9.9, 16.3 Hz, CHAHB), 1.40 (3 H, S , CH?), 1.15 (3 H, s, CH,); "C NMR (62.9 MHz, Me,SO-d,) 6 171.8 (C=O), 163.0, 141.7, 138.9, 125.6, 119.3, 109.8 (Ar), 91.9 (OCH), 43.0 (C), 35.0 (CH,), 26.0 (CH,), 23.1 (CH,); MS (found Mt 251.0804, CI2H13N05 requires M 251.0794), m / z 251 (28, M+), 236 (51, M Me), 190 (100). Anal. Calcd for C12H,,NOS: C, 57.4; H, 5.20; N, 5.6. Found: C, 57.7; H , 5.30; N , 5.5. trarans-4-Methyl-4-(2-hydroxyphenyI)pent-2-enoic Acid (7a). n-Butyllithium (0.76 mL of a 1.6 M solution in hexane, 1.2 mmol) was added to a stirred solution of diisopropylamine (0.17 mL, 1.2 mmol) in dry THF (2 mL) under nitrogen at -78 OC. After I O min, 8a (0.1 g, 0.49 mmol) in dry T H F (3 mL) was added and stirring continued for 1 h. The mixture was acidified with concentrated HCI and extracted with dichloromethane (3 X 15 mL). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give a greater than 90% yield of 7a, contaminated with starting material 8a. This material was not purified further: 'H NMR (80 MHz, CDCI,) 6 7.40 (1 H, dd, J = 15.9 Hz, CH=CHCO,H), 7.28-6.65 (4 H, m, Ar), 5.80 (1 H, d, J =

J . Am. Chem. Soc., Vol. 1IO, No. 19, 1988 6501

Phenolate Oxygen Addition to Activated C=C 15.9 Hz, CHzCHCOZH), 1.52 (6 H, S, CH,). Prepared in a similar fashion was trans-4-methyl-4-(5-bromo-2hydroxypheny1)pent-2-enoicacid (7b): IR (liquid film) 1690 cm-' (C= 0 ) ;IH N M R (250 MHz, CDCIp) 6 7.25-7.20 (2 H, m, Ar), 7.14 (1 H, d , J = 15.9 Hz, CH=CHCO,H), 6.76 (1 H, d, J = 6 Hz, Ar), 5.58 (1 H, d, J = 15.9 Hz, CH=CHCOzH), 1.43 (6 H, S, CHp). Dipotassium ~-4-Methyl-4-(5-Ntro-2-hydroxy~yhenyt)pent-2-enoate (7c). 8c (50 mg, 0.2 mmol) was added to a stirred solution of potassium rerr-butoxide (100 mg, 0.89 mmol) in dry T H F (4 mL) under nitrogen, and the mixture was heated under reflux for 20 h. The mixture was filtered and the solid washed with T H F (3 X 5 mL). This material was not purified further: UV (1 M aqueous KOH) 425 nm (e 10000); 'H N M R (90 MHz, Me2SO-d6) 6 7.73-7.60 (2 H, m, Ar), 6.72 (1 H, d, J = 16.5 Hz, CH=COzK), 5.87 (1 H, d, J = 10 Hz, Ar), 5.48 (1 H , d, J = 16.5 Hz, CHeCHCOzK), 1.33 (6 H , S, CH,). Kinetics. Rate constants were measured at 39 OC in water at ionic strength 1.0 M (KCI) on a Gilford 2600 spectrophotometer equipped with a Thermoset temperature control unit. Some data for 7a were measured at an ionic strength of 0.2 M. The change in ionic strength does not affect the rate significantly. Kinetic runs were started by injecting 1 pL of a stock solution of the substrate into 0.25 mL of preheated buffer solution in 0.3-mL capacity quartz cuvettes. Stock solutions of 7a and 7b (ca. 20 mg/mL) were made up in dioxane and acetonitrile, respectively. For 7c, the solution (ca. 10 mg/mL of the dipotassium salt) was in dimethyl sulfoxide. In all cases the medium contained 99% acid form) concentration; carrier buffer concentration is constant. M E , N-morpholinoethanesulfonate. dMPOS, N-morpholinopropanesulfonate. Correlation coefficients of second-order plots are better than 0.996, except for c r = 0.993. Table 111. Observed Rate Constants for the Buffer-Catalyzed Cyclization of 7s. at 39 OC and Ionic Strength 1.0 M (KClI no. of runs no. of runs buffer (concn. 104k2b, buffer (concn. (% free base) range, M) pH 104kn4.s-' M-' s-l (% free base) range, M) DH

104kn', s-I

104k2b,

M-1 s-I

quinuclidine (20) 5 (0.1-0.5) 110.52 52.1 f 0.50" 26.2 f 1.50 ethanolamine (20) 4 (0.1-1.0) 8.68 3.59 f 0.23 11.1 f 0.40 ethylamine (15) 5 (0.2-1.0) 9.70 13.0 f 0.40 13.0 f 0.60 TRISc (80) 4 (0.04-0.4) 8.57 2.63 f 0.04 4.41 f 0.18 TRIS (50) 4 (0.05-0.5) n-propylamine (15) 5 (0.2-1 .O) 9.62 12.9 f 0.20 7.95 1.89 f 0.04 6.77 f 0.14 6.95 f 0.28 3-propanolamine (35) 5 (0.2-1.0) 9.67 13.1 f 0.40 13.9 f 0.60 TRIS (20) 4 (0.05-0.5) 7.35 1.84 f 0.06 8.93 f 0.22 ethanolamine (80) 4 (0.1-1.0) 9.91 21.7 f 0.10 7.81 f 0.24 TRIS (10) 5 (0.05-0.25) 7.01 1.82 f 0.05 9.75 f 0.29 ethanolamine (65) 5 (0.2-1.0) 9.64 11.2 f 0.30 12.6 i 0.50 3-quinuclidinone (20) 5 (0.01-0.05) 6.7 1 1.92 f 0.07 9.26 f 2.20 9.33 7.76 f 0.13 12.2 i 0.20 ethanolamine (50) 4 (0.1-1.0) acetic acid (50) 5 (0.1-0.5) 4.61 0.954 f 0.042 6.23 f 0.13 ethanolamine (35) 4 (0.2-0.8) 9.12 5.17 f 0.18 12.2 i 0.30 cvanoacetic acid (201 5 (0.2-1.0) -1.8 0.279 f 0.008 0.321 f 0.011 Intercept and bslope of plot of pseudo-first-order rate constants against total buffer concentration. CTRIS, tris(hydroxymethy1)aminomethane hydrochloride. Correlation coefficients for second-order plots were all better than 0.997, except for d r = 0.995. Table IV. Calculation of Second-Order Rate Constants (M-' s-I) for the Buffer-Catalyzed Cyclization of the Dianion of 7a, at 39 'C and Ionic Strength 1.0 M (KCI) buffer 104kmonOa a (% free base) pKBH 0 1 0 4 k 0 ~(b) ' PH f d i e (c) 104kmonOF onod ( d) 103kdie (e) quinuclidine (20) 11.5 18.9 26.2 10.52 0.403 9.03 5.33 ethylamine (15) 10.5 3.99 13.0 9.70 0.093 3.08 12.6 3-propanolamine (35) 9.9 8.12 13.9 9.67 0.087 4.82 16.1 ethanolamine (80) 9.4 10.1 7.81 9.91 0.142 1.73 21.4 ethanolamine (65) 9.4 10.1 12.6 9.64 0.082 3.25 32.5 "Apparent second-order rate constant for general-acid catalysis of the cyclization of the monoanion. Data from Table 11 corrected for the small amount of substrate present in the neutral acid form. bData from Table 111. cFraction of 7a present as dianion at pH given. dContribution from the buffer acid-catalyzed reaction of the monoanion. Subtracting this from the figure in column (b) gives the corresponding contribution from the dianion reaction. 'Calculated (in column headings) as ( W ) / c , which is finally divided by the fraction of free acid in the buffer. Table V. Derived Second-Order Rate Constants kBH+ (M-' s-I) for the Buffer-Catalyzed Cyclization of 7a, 7b, and 7c, at 39 "C and Ionic Strength 1.0 M (KCI) 7a 7b 7c buffer base, B pKBH4 monoanionb dianion monoaniod dianion monoanionb dianion quinuclidine 11.5 2550 5.33 x 10-3 582 2.01 x 10-3 2.13 1.47 x 10-5 ethylamine 10.5 538 1.26 X 148 1.89 X lo-' 0.385 1.08 x 10-5 3-quinuclidinol 10.0 5670 1376 5.75 3-propanolamine 9.9 1095 1.61 X 23 1 3.55 x 10-3 0.80 1.97 X ethanolamine 9.4 1360 2.70 X 333 5.75 x 10-3 0.92 3.58 X 10" 3-chloroquinuclidine 9.0 8230 2226 11.1 3-quinuclidinone 7.5 16500 4240 18.0 acetate 4.6 3180 720 2.86 "pKa's of quinuclidines at 25 "C, ionic strength 1.0 M (KC1) taken from Gresser, M.J.; Jencks, W. P. J . Am. Chem. Soc. 1977, 99, 6963. pKa's of primary amines and acetate calculated from the observed pH values of buffer solutions. bSecond-order rate constants calculated for the reaction of the minor (phenol O-/COOH) ionic form.

obtained at higher pH (for the reaction of the dianion) for the monoanion reaction. Because the second pK, of 7a is so high (10.69), only a very limited range of general acids could be used, and only measurements made above pH 9.5 (>5% of dianion) were useful. The full set of data for buffer catalysis of the cyclization of 7a is given in Table 111, and the calculation of the rate constants for the dianion reaction, from data sets measured a t pH >9.5, is summarized in Table IV. As discussed below, it is reasonable to assume that the monoanion reacts through the thermodynamically less favorable phenolate-COOH tautomer. The derived

rate constants for general-acid catalysis of the reactions of the monoanions of 7a, 7b, and 7c given in Table V have been calculated on this basis and can thus be compared directly with those for the corresponding dianion reactions. Isotope Effects. Data for the kinetic solvent isotope effects appear in Table VI. The isotope effects for the water-catalyzed dianion reactions were determined in the region of pH where the substrates were completely ionized ([H']