Grignard reagent formation from aryl halides. There is no aryl radical intermediate along the dominant reaction channel

www.elsevier.nl/locate/ica Inorganica Chimica Acta 296 (1999) 52 – 66

Grignard reagent formation from aryl halides. There is no aryl radical intermediate along the dominant reaction channel John F. Garst a,*, J. Ronald Boone b, Lisa Webb b, Kathryn Easton Lawrence a, James T. Baxter c, Ferenc Ungva´ry d a Department of Chemistry, The Uni6ersity of Georgia, Athens, GA 30602, USA Department of Chemistry, Da6id Lipscomb Uni6ersity, Nash6ille, TN 37203, USA c Department of Chemistry, Valdosta State Uni6ersity, Valdosta, GA, USA d Department of Organic Chemistry, Uni6ersity of Veszpre´m, and Research Group for Petrochemistry of the Hungarian Academy of Sciences, 8200 Veszpre´m, Hungary b

Received 4 May 1999; accepted 9 August 1999

Abstract For Grignard reagent formation from magnesium and an aliphatic halide RX in an ether solvent, a route through R’ is the major pathway. Part of the evidence is that by-products of side reactions of R’ are formed in substantial yields. Similar reactions of phenyl and o-(3-butenyl)phenyl halides give very low (sometimes trace) yields of by-products derived from side reactions of R’, despite the fact that aryl R’ are much more reactive than alkyl in both solvent attack and cyclization [o-(3-butenyl)phenyl case]. Grignard reactions of aryl halides appear to proceed largely through a pathway along which R’ is not an intermediate. This is probably a dianion pathway, that is, one along which RX2 − is an intermediate or transition state. © 1999 Elsevier Science S.A. All rights reserved. Keywords: Grignard reagent; Aryl halides; Aryl radical; Magnesium; Phenyl chloride; Phenyl bromide; Phenyl iodide

1. Introduction Mg0 reacts with an organic halide RX in a suitable solvent, usually diethyl ether (DEE) or tetrahydrofuran (THF), to form a Grignard reagent RMgX [1,2]. This may be the nontrivial reaction used most often in synthetic chemistry. There have been many mechanistic studies of Grignard reactions of alkyl, cyclopropyl, and vinyl halides, but few of aryl halides. The present study shows that the mechanisms of reactions of aryl halides differ from those of alkyl halides. By 1954, it was clear that Grignard reactions of typical alkyl halides proceeded through intermediate radicals R’ (pathway R) [1]. Abundant verification has since followed [3].

* Corresponding author. Fax: +1-706-542 2673.

For reactions of typical alkyl and cyclopropyl halides, compelling evidence contradicts the hypothesis that the intermediate radical R’ remains adsorbed at the magnesium surface MgZ [A (adsorption) model] and supports the D (diffusion) model instead, in which R’ diffuses in solution [4]. The A model predicts that deuterating the solvent SH (DEE or THF) will not increase the yield (RMgX) in Grignard reactions of cyclopropyl bromide, but in fact it does, to an extent that is predicted quantitatively, and correctly, by the D model. While the A model does not afford quantitative

0020-1693/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved. PII: S 0 0 2 0 - 1 6 9 3 ( 9 9 ) 0 0 3 5 1 - 5

J.F. Garst et al. / Inorganica Chimica Acta 296 (1999) 52–66

predictions of product distributions, quantitative Dmodel predictions agree, within experimental error, with observed product distributions from reactions of 5-hexenyl bromide in DEE and THF [5]. Indeed, observed product distributions from Grignard reactions of cyclopropyl and 5-hexenyl bromide, reactions of other alkyl halides giving isomerizing intermediate radicals R’ [6], and reactions of alkyl halides in the presence of a radical trap (DCPH (dicyclohexylphosphine) [7] or TMPO (2,2,6,6-tetramethylpiperidine-Noxyl) [8]) all agree quantitatively with D-model calculations in which the characteristic lifetime tG of R’, as limited by r, is near 3× 10 − 8 s [9].

When radical–radical reactions of R’ are not significant, the product distribution may be determined by the competition between p [a (pseudo-)first-order reaction (rate constant kP) of R’ (isomerization, solvent attack, trapping)] and r. The competition is described by Eq. (1) (infinite-dilution D model), where q is the yield ratio (P)/ (RMgX) [5,9–11]. The square-root dependence arises from the diffusion of R’ in solution between the times that it is formed and reduced at the Mg surface. q=(kPtG)1/2

(1)

Eq. (1) is a version of Eq. (6) of Garst, Deutch and Whitesides [10], q=(1/d +s)(kP/D)1/2, where d is k/D, k is the activation-control heterogeneous rate constant for the reduction of R’ at the Mg surface, D is the diffusion coefficient of R’, and s is the distance from the Mg surface at which R’ is formed. Setting s to zero and identifying tG as 1/Dd [2] gives Eq. (1). tG is defined so that q = 1 when tG =tP, where tP is the characteristic lifetime, 1/kP, of R’, as limited by p. Observed data for typical alkyl halides are fit by d= 0.01 A, − 1 [5,6,10,11]. For D = 3 ×10 − 5 cm2 s − 1 (3 × 1011 A, 2 s − 1), a typical value, this corresponds to tG =3 ×10 − 8 s. A similar value, with Eq. (1), describes reactions of cyclopropyl bromides in DEE and THF [4,12], suggesting that tG may be independent of the nature of R’ (perhaps controlled instead by the nature of the medium or the coupling of r with other corrosion steps). If Grignard reactions of aryl halides proceeded through pathway R, as appears to be generally believed, then cyclopropyl halides would be appropriate models for phenyl halides PhX. Both would give s radicals R’ of similar reactivity [13,14].

53

Similarly, 5-hexenyl halides would be appropriate models for o-(3-butenyl)phenyl halides. Both would give radicals R’ that cyclize to radicals Q’ with known rate constants [15,16].

As noted above, Grignard reactions of cyclopropyl and 5-hexenyl halides have been studied previously [5,10,12]. Accordingly, we have examined Grignard reactions of phenyl and o-(3-butenyl)phenyl halides. If the reactions follow pathway R, then Eq. (1) provides quantitative predictions of product distributions from Grignard reactions of phenyl and o-(3butenyl)phenyl halides at 37°C. For THF, it is predicted that the yield of PhMgX from PhX will be 37%, limited by the occurrence of 63% solvent attack s [Eq. (1) with kP = kS = 1× 108 s − 1 (estimated for 37°C from the measured value 6× 107 s − 1 at 25°C) and tG = 3× 10 − 8 s; q= 1.7] (Table 1, entry for ‘model’). For DEE, it is predicted that the yield of PhMgX from a phenyl halide PhX will be 51%, limited by the occurrence of 49% solvent attack s [Eq. (1) with kP = kS = 3×107 s − 1 (estimated as slightly less reactive than THF) and tG = 3×10 − 8 s; q= 0.95] (Table 2, entry for ‘model’). For THF, it is predicted that the yield of RMgX for a o-(3-butenyl)phenyl halide RX will be 20%, limited by the occurrence of 64% cyclization of R’ to Q’ (indanylmethyl), giving 64% QMgX, and 16% solvent attack s {Eq. (1) with kP = kI + kS = [(4× 108) +(1× 108)] s − 1 and tG = 3× 10 − 8 s; q= 3.87= [(QMgX)+ (s)]/(RMgX); (QMgX) = (4/5)[(QMgX) + (s)]} (Table 5, entry for ‘model’). A similar calculation for DEE (same parameters except kS, kS = 3×107 s − 1) predicts (RMgX)= 22%, (QMgX) = 73%, and (s) = 5% (Table 6, entry for ‘model’). It is found that these predictions fail dramatically. Clearly, cyclopropyl and 5-hexenyl bromides are not good models for phenyl and o-(3-butenyl)phenyl halides in Grignard reactions. The mechanisms of Grignard reactions of aryl halides are fundamentally different from those of alkyl halides.

J.F. Garst et al. / Inorganica Chimica Acta 296 (1999) 52–66

54

Table 1 Products of Grignard reactions of phenyl halides (RX) in THF a Experiment

X

[RX]0

Model g U97-62 U97-66 U97-59 U97-58 U97-67 U97-68 U97-61 U97-60 U97-63 U97-64 U97-78

Cl Cl Br Br Br Br I I I I I

0 0.2 1.0 0.2 0.2 1.0 1.0 0.2 0.2 0.2 1.0 0.2

b

[MgCl2]0 b

Temperature c

Time d

0.50 0.50 0 0.50 0 0.50 0 0.50 0 0 0.50

37 37 37 37 37 37 37 37 37 37 37 67

16 16 0.5 0.5 0.5 0.5 0.5 0.5 6.0 6.0 0.5

(RMgBr) e 37 99 97 100 100 99 99 64 h 95 103 97 98

(RH) f

(RR) f

37 103 92 106 104 99 97 70 h 102 104 97 102

0.78 3.2 0.1 0.1 0.2 0.1 0.3 h 0.2 0.8 1.2 0.5

(SS) f

63 0 0 0 0 0 0 0h 0 0 0 0

a

For RMgX, RH, and RR, tabulated values are percentages of R groups, of the RX consumed, accounted for in the product. No SS or RS was detected in any experiment. b Initial concentration, M. c Temperature, °C. d Reaction time, h. e By titration [29]. f By gas chromatography after acidic quenching. No SS or RS was detected in any experiment. Control experiments indicate that a yield of SS as low as 0.03% could have been detected. The value for SS in italics is the calculated percentage of intermediate radicals R’ that attack the solvent. g Model: Eq. (1). See text for details. h Probably inaccurate, due to less than 30% conversion of RI in this short reaction time. MgI2 is insoluble in THF. Its precipitation on MgZ slows reactions of RI. Table 2 Products of Grignard reactions of phenyl halides (RX) in DEE at 37°C a Experiment

X

[RX]0

Model e AU-166 AU-169 U97-74 U97-75 U97-77 U97-76 AU-167 AU-170 U97-69 U97-73 U97-70 U97-71 U97-72

Br Br Br Br Br Br I I I I I I I

0 0.2 0.2 0.2 0.2 1.0 1.0 0.2 0.2 0.2 0.2 0.2 1.0 1.0

b

[MgBr2]0 b

0 0 0 2.6 0 2.6 0 0 0 0 2.6 0 2.6

(RMgBr) c 51 91 76 87 87 98 80 65 66 88 70 94

(RH) d

(RR) d

1.6

49 0.7

2.4 0.6 5.1 2.9 5.9

0.8 0 1.4 0.1 3.3

7.6 7.6 0.5 13.1 3.8

3.1 3.2 0 4.1 0.3

51

3. 4 94 100 90 97 7. 0 89 86 82 85 99

(SS) d

a For RMgX, RH, and RR, tabulated values are percentages of R groups, of the RX consumed, accounted for in the product. For SS, tabulated values are percentages of R groups, of the RX consumed, accounted for as S residues (reflecting solvent attack). Reaction time: 0.5 h. MgI2 is soluble in DEE. b Initial concentration/M. c By titration [29]. d By gas chromatography after acidic quenching. Values for RH in italics are yields before quenching. The value for SS in italics is the calculated percentage of intermediate radicals R’ that attack the solvent. e Model: Eq. (1). See text for details.

2. Experimental

2.1. Grignard reactions Grignard reactions were carried out under dry nitrogen in a thermostatted glass reactor fitted with a reflux

condenser (5°C) and a silicon-rubber-capped stopcock, using a Teflon-coated magnetic stirring bar. All parts were oven-dried and assembled hot with silicone grease. To the stirred and thermostatted mixture of the solvent (5–10 ml freshly distilled absolute DEE or THF from blue or purple solutions of benzophenone ketyl or

J.F. Garst et al. / Inorganica Chimica Acta 296 (1999) 52–66

dianion), n-octane (10 ml, Aldrich, 99%+ ; internal standard for gas chromatography), and magnesium turnings (0.5 to 1.0 g, Strem, 2N8), the organic halide (1 – 10 mmol, dried and freshly distilled under nitrogen) was injected using a TLL-type syringe. In experiments using solutions of a magnesium halides, the MgBr2 or MgCl2 was prepared in situ from magnesium turnings and 1,2-dibromoethane or 1,2dichloroethane, respectively, prior to the addition of the organic halide for the Grignard reaction. For analysis, a 0.1 ml portion of a solution of anhydrous 1,10-phenanthroline (Aldrich, 99%+ ) in DEE or THF (20 mg in 20 ml solvent) was added. The red mixture was titrated to the sharp, colorless endpoint with anhydrous (9)-2-butanol (Aldrich, 99%+) delivered from a microburette through Teflon spaghetti tubing and a needle through the capped stopcock on the reaction vessel. The titrated reaction mixture was quenched with cold brine (0.8 – 3 ml) and the organic layer was analyzed by gas chromatography (Hewlett-Packard HP 5890 with a 30-m, 0.32 mm i.d., SPB-1 fused-silica capillary column, helium carrier gas, flame-ionization detector, and splitless injection). Components were identified by co-injection of authentic samples and GC-MS (Hewlett-Packard 5970 MSD). Quantitative analyses were based on measured response factors using model mixtures.

2.2. o-(3 -Butenyl)phenyl halides [1 -halo-2 -(3 -butenyl)benzenes] [17,18] 1-Chloro-, 1-bromo-, and 1-iodo-2-(3-butenyl)benzenes were synthesized by reactions of excess allylmagnesium bromide with appropriate 1-halo-2(halomethyl)benzenes (o-halobenzyl halides).

2.3. Allylmagnesium bromide [19] Allyl bromide (Aldrich) was distilled (b.p. 69.5– 70°C) and stored under nitrogen. A solution of 12.6 g allyl bromide in 12 ml in anhydrous DEE (Fisher) was slowly added to 6.00 g of magnesium metal in 132 ml DEE under nitrogen, so as to maintain a steady reflux. After spontaneous refluxing ceased, the mixture was heated to reflux for 30 min. Acidimetric analysis of the resulting solution showed a Grignard reagent concentration of 0.47 M (69% yield). The allylmagnesium bromide (138 ml, 65 mmol) was transferred by syringe to another flask. Repeated preparations of allylmagnesium bromide under these conditions gave yields very close to 69% by acidimetric analyses and also showed an 82% consumption of the theoretical amount of magnesium metal. Yields are probably low because of the formation of biallyl [20].

55

2.3.1. o-(3 -Butenyl)phenyl chloride A solution of 12.4 g (60.4 mmol) of o-chlorobenzyl bromide in 8 ml of ether was slowly added to 96 mmol of allylmagnesium bromide in 150 ml DEE. The reaction was refluxed an additional hour and allowed to stand overnight. The reaction was cautiously quenched with 5% HCl, and the product was extracted with ether and washed with 10% NaCl. The ether solution was dried with anhydrous MgSO4. The ether was removed by distillation, and the residual oil was distilled (97–99°C, 19.5 torr) to give 4.67 g (28.0 mmol, 46% yield) of a colorless liquid. Gas chromatographic analysis showed a large peak (\98.6%) and an additional peak ( B 1.4%) with the retention time of (3-butenyl)benzene. 1H NMR (250 MHz, CDCl3): d 7.1–7.4 (m, 4H, ArH), 5.89 (m, 1H, CH), 5.05 (m, 2H, CH2), 2.84 (m, 2H, ArCH2), 2.39 (m, 2H, CH2CH) ppm. Anal. Calc. for C10H11Cl: C, 72.07; H, 6.65; Cl, 21.27. Found: C, 71.99; H, 6.67; Cl 21.36%. 2.4. o-(3 -Butenyl)phenyl bromide Under nitrogen and with stirring, 5.05 g (20.2 mmol) of o-bromobenzyl bromide in 15 ml of ether were slowly added to 65 mmol of allylmagnesium bromide in 138 ml of ether over a period of 30 min. The resulting mixture was refluxed for 1.5 h then allowed to stand overnight. The reaction was quenched cautiously with 5% HCl, and the product extracted with ether and washed with 10% NaCl. The ether solution was dried with anhydrous MgSO4. The ether was removed by distillation to give an oil. This reaction was repeated on the same scale. The combined crude products were subjected to vacuum distillation (111–114°C, 19.5 torr) to give 7.07 g (33.5 mmol, 83% yield) of a colorless liquid product. Gas chromatographic analysis showed a single peak. 1H NMR (250 MHz, CDCl3): d 7.54 (m, 1H, ArH), 7.24 (m, 2H, ArH), 7.05 (m, 1H, ArH), 5.90 (m, 1H, CH), 5.05 (m, 2H, CH2), 2.84 (m, 2H, ArCH2), 2.40 (m, 2H, CH2CH) ppm. Calc. for C10H11Br: C, 56.90; H, 5.25; Br, 37.85%. Found: C, 57.81; H, 5.21; Br, 37.71%.

2.5. o-(3 -Butenyl)phenyl iodide A solution of 8.24 g (32.6 mmol) of o-iodobenzyl chloride in 15 ml of ether was slowly added to 60 mmol of allylmagnesium bromide in 150 ml DEE. The reaction was refluxed an additional hour and allowed to stand overnight. The reaction was cautiously quenched with 5% HCl, and the product was extracted with ether and washed with 10% NaCl. The ether solution was dried with anhydrous MgSO4. The ether was removed by distillation, and the residual oil

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was subjected to vacuum distillation (129 – 139.5°C, 19 torr) to give 5.65 g (26.7 mmol, 82% yield) of a colorless liquid product. Gas chromatographic analysis showed a single peak. 1H NMR (250 MHz, CDCl3): d 7.82 (m, 1H, ArH), 7.20 (m, 2H, ArH), 6.89 (m, 1H, ArH), 5.80 (m, 1H, CH), 5.05 (m, 2H, CH2), 2.81 (m, 2H, ArCH2), 2.35 (m, 2H, CH2CH) ppm. Calc. for C10H11I: C, 46.54; H, 4.30; I, 49.17. Found: C, 46.58; H, 4.30; I, 49.17%.

2.6. (3 -Butenyl)benzene A solution of 5.50 g (43.4 mmol) benzyl chloride in 5 ml ether was added to 79 mmol allyl magnesium bromide in 150 ml ether over 45 min. The reaction was refluxed an additional hour and allowed to stand overnight. The reaction was cautiously quenched with 5% HCl, and the product was extracted with ether and washed with 10% NaCl. The ether solution was dried with anhydrous MgSO4. The ether was removed by distillation, and the residual oil weighed 5.52 g (41.8 mmol, 96% crude) and was distilled (176–176.5°C) at atmospheric pressure. Gas chromatographic analysis showed a single peak (\ 99%) with a few trace peaks. 1H NMR (250 MHz, CDCl3): d 7.2 – 7.4 (m, 5H, ArH), 5.92 (m, 1H, CH), 5.05 (m, 2H, CH2), 2.76 (m, 2H, ArCH2), 2.42 (m, 2H, CH2CH) ppm.

2.7. Indanylmethyl halides [1 -(halomethyl)indanes] Indanylmethyl bromide was prepared from 1-indanone by a Wittig reaction, giving 1-methyleneindane, and subsequent hydroboration/oxidation to 1-(hydroxymethyl)indane, tosylation to 1-(tosyloxymethyl)indane, and displacement of tosylate by bromide. Indanylmethyl iodide was prepared from indanylmethyl bromide by a reaction with sodium iodide in acetone.

2.8. 1 -Methyleneindane [21] 1-Methyleneindane was prepared in 62% yield (b.p.4 = 65°C; m.p. ca. 40°C) from the Wittig reaction of 1-indanone and methylenetriphenylphosphine [22] in DMSO.

2.9. 1 -(Hydroxymethyl)indane [23] 1-(Hydroxymethyl)indane was prepared in 82% yield (b.p.3 =105°C) from 1-methyleneindane by hydroboration and subsequent oxidation with H2O2 [24].

2.10. 1 -(Tosyloxymethyl)indane To a solution of 1-(hydroxymethyl)indane (5.37 g, 36.2 mmol) in anhydrous pyridine (26 ml) under a nitrogen atmosphere, p-toluenesulfonyl chloride (7.64 g, 40 mmol) was added at −5°C and stirred for 3 h at 0°C [25]. Diluting the reaction mixture with ice water (50 ml) and

extracting with cold (0°C) chloroform (3× 50 ml) gave a colorless organic phase which was washed with cold (0°C) 1 M sulfuric acid (5× 50 ml), then with ice water (2×50 ml) and finally with cold (0°C) KHCO3 (10% in water) solution (2× 50 ml). Drying over anhydrous MgSO4 and removing the solvent in vacuo resulted in a colorless oil (10.84 g) in 98% yield. Anal. Calc. for C17H18O3S: C, 67.52; H, 6.00; S, 10.60. Found: C, 67.81; H, 6.09; S, 10.38%. 1H NMR (300 MHz, CDCl3): d 7.69–7.25 (dd, 4H, aromatic proton in the tosyl part), 7.06 (m, 4H, ArH), 4.15 (m, 1H, CHaHbOTs), 3.95 (m, 1H, CHaHb OTs), 3.41 (m, 1H, CH), 2.79 (m, 2H, ArCH2), 2.37 (s, 3H, CH3), 2.15 (m, 1H, CHaHbCH), 1.76 (m, 1H, CHaHbCH) ppm. 13C NMR (75.4 MHz, CDCl3): d 144.70, 144.25, 141.70, 132.87 (quaternary aromatic carbons); 129.78, 127.84, 127.36, 126.27, 124.71, 124.15 (protonated aromatic carbons); 72.77 (CH2OTs); 44.19 (CH); 30.91, 28.49 (ArCH2CH2); 21.58 (CH3) ppm.

2.11. Indanylmethyl bromide To a solution of LiBr (8.2 g, 94.2 mmol) in dry acetone (80 ml), 1-(tosyloxymethyl)indane (25.5 g, 84.4 mmol) in dry acetone (20 ml) was added at once and refluxed for 20 h [26]. Filtration of the resulting slurry gave 14.68 g of a white solid (lithium p-toluenesulfonate) and a pale yellow solution. Removing the solvent under vacuum gave 16.56 g of a yellow oil, which was fractionally distilled (68°C, 1 torr), giving 11.64 g indanylmethyl bromide (50.7% yield). Calc. for C10H11Br: C, 56.90; H, 5.25; Br, 37.85. Found: C, 57.85; H, 5.33; Br, 36.68%. 1H NMR (300 MHz, CDCl3): d 7.4 (m, 4H, ArH), 3.8 (m, 1H, CHaHbBr), 3.6 (m, 1H, CH), 3.5 (m, 1H, CHaHbBr), 2.9 (m, 2H, ArCH2), 2.4 (m, 1H, ArCHCHaHb), 2.0 (m, 1H, ArCH2CHaHb) ppm. 13C NMR (75.4 MHz, CDCl3): d 144.33, 143.67 (quaternary aromatic carbons); 127.35, 126.29, 124.85, 123.91 (protonated aromatic carbons); 47.28 (CH2Br); 37.37 (CH); 31.22, 30.75 (ArCH2CH2) ppm.

2.12. Indanylmethyl iodide To a solution of anhydrous NaI (4.5 g, 30 mmol) in 30 ml dry acetone under an atmosphere of N2, indanylmethyl bromide (5.06 g, 24 mmol) was added and refluxed for 18 h [27]. Filtration of the reaction mixture using a P4 frit gave a white solid and a dark yellow filtrate. The filtrate was concentrated at room temperature under vacuum, dissolved in ether (10 ml), and washed with aqueous sodium thiosulfate. After drying the organic phase over anhydrous CaCl2 and removing the solvent by distillation, fractional vacuum distillation (81–82°C, 1 torr) gave indanylmethyl iodide as a yellow liquid (4.6 g, 17.8 mmol, 74% yield). Calc. for C10H11I: C, 46.54; H, 4.30; I, 49.17. Found: C, 47.60; H, 4.36; I, 48.00%. 1H NMR (300 MHz, CDCl3): d 7.2 (m, 4H,

J.F. Garst et al. / Inorganica Chimica Acta 296 (1999) 52–66

57

Table 3 Products of Grignard reactions of indanylmethyl bromide and iodide (QX) in THF at 37°C a Experiment

X

[MgCl2]0

U97-3 U97-2 U97-7 U97-6 U97-8 U97-52 U97-53 U97-57

Br Br Br Br Br I I I

0 0 0 0 0.50 0 0.50 0.50

b

Time c

(QMgBr) d

(QH) e

[Q(–H)] e

(QOH) e

(QQ) e

0.5 1.0 2.5 5.0 2.5 16.0 1.0 6.0

63 63 67 67 76 53 54 52

76 82 79 79 95 72 69 75

1.0 1.3 1.0 1.0 1.0 3.3 5.0 5.7

6.9 9.7 6.9 7.3 6.9 4.9 6.5 5.1

6.7 9.5 4.0 4.1 3.3 15 16 9.8

a

Initial concentration of indanylmethyl halide = 0.20 M. For QMgX, QH, Q(–H), QOH, and QQ, tabulated values are percentages of Q groups, of the QX consumed, accounted for in the product. No product other than those shown was found. b Initial concentration, M. c Reaction time, h. Passivation by insoluble MgI2 lengthens required reaction times for RI. d By titration [29]. e By gas chromatography after acidic quenching. QH = methylindane. Q(–H) = methyleneindane. QOH =indanylmethyl alcohol. QQ = bis(indanylmethyl).

ArH), 3.6 (m, 1H, CHaHbI), 3.4 (m, 1H, CH), 3.3 (m, 1H, CHaHbI), 2.9 (m, 2H, ArCH2), 2.4 (m, 1H, CHaHbCH), 1.9 (m, 1H, CHaHbCH) ppm. 13C NMR (75.4 MHz, CDCl3): 144.45, 144.24 (quaternary aromatic carbons); 127.25, 126.32, 124.94, 123.71 (protonated aromatic carbons); 47.28 (CH2I); 33.26, 30.54 (ArCH2CH2); 12.24 (CH) ppm.

2.13. 1 -Methylindane A solution of 22.8 g (160 mmol) methyl iodide in 125 ml DEE was slowly added to 4.30 g (177 mmol) of magnesium metal, so as to maintain a steady reflux. After stirring one additional hour, 15.0 g of 1-indanone in 30 ml DEE were added slowly. A precipitate formed and dissipated with each drop. About midway during the addition, the precipitate became permanent. The reaction was refluxed an additional hour and allowed to stand overnight. The reaction was cautiously quenched with 5% HCl, and the product was extracted with ether and washed with 10% NaCl. The ether solution was dried with anhydrous MgSO4. The ether was removed by distillation. By error, much of the product was dehydrated and polymerized, but a small amount of material was distilled at 89 –98°C (18 torr), which proved to be 3-methylindene by 1H NMR spectroscopy. 1H NMR (250 MHz, CDCl3): d 7.2–7.6 (m, 4H, ArH), 6.26 – 6.28 (m, 1H, CH), 3.37 –3.39 (m, 2H, ArCH2), 2.23 – 2.25 (m, 3H, CH3) ppm. A solution of 0.47 g (3.6 mmol) of 3-methylindene in 20 ml of hexane and 0.12 g of 5% Pd on carbon was hydrogenated; 90 ml (3.7 mmol) of hydrogen was taken up at ambient conditions. The solution was separated from the catalyst, the hexane was distilled off, and the residual oil subjected to microscale vacuum distillation (78 – 80°C, 18 torr); 0.24 g (1.8 mmol) of colorless liquid was collected. Gas chromatographic analysis showed one major component, \98%. NMR spectra of the product

were consistent with 1-methylindane. 1H NMR (250 MHz, CDCl3): d 7.2 (m, 4H, ArH), 3.20 (m, 1H), 2.88 (m, 2H), 2.33 (m, 1H), 1.63 (m, 1H) (ArCH2CH2 and ArCH), 1.31 (d, 3H, CH3) ppm.

2.14. 5 -Hexenyl halides 5-Hexenyl halides prepared previously were dried (molecular sieves), purified by distillation, assayed by GC, and used as \ 99% pure compounds.

3. Results Contrary to the model calculation that predicts 63% solvent attack s, none is detected in the Grignard reaction of PhCl, PhBr, or PhI in THF (Table 1; no SS or RS). Contrary to the similar model calculation that predicts 49% s, a much smaller amount (5 7%) is detected in the Grignard reaction of PhBr or PhI in DEE (Table 2; (PhH) prior to acidic quenching and (SS)). The attempted reaction of PhCl did not initiate. In THF or DEE, the Grignard reaction of an indanylmethyl halide QBr or QI, followed by acidic quenching, gives no ring-opened products (Tables 3 and 4). Therefore QMgX does not open to RMgX under our reaction conditions. Product distributions closely resemble those of Grignard reactions of other typical alkyl halides, including the formation of significant amounts of coupling product QQ and accompanying disproportionation products and the absence of detectable products of solvent attack (Tables 3 and 4). The QOH found in these experiments could be a product of oxidation of QMgX, possibly formed during quenching, or it could be a product of a reaction of Mg(OH)2, the major component of the adventitious ‘oxide’ layer on the surface of Mg [28], with QX.

J.F. Garst et al. / Inorganica Chimica Acta 296 (1999) 52–66

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Table 4 Products of Grignard reactions of indanylmethyl bromide and iodide (QX) in DEE at 37°C a Experiment

X

[MgBr2]0

U97-10 U97-9 U96-39 U97-11 U97-12 U97-54 U97-56

Br Br Br Br Br I I

0 0 0 0 2.6 0 2.6

b

Time c

(QMgBr) d

(QH) e

(Q(–H)) e

(QOH) e

(QQ) e

0.5 2.5 2.5 5.0 2.5 6.0 1.0

56 56 56 56 77 33 76

77 71 69 78 83 56 89

1.8 1.6 1.3 2.0 0.9 4.2 1.3

3.2 2.3 4.6 8.1 2.7 4.2 1.4

3.0 0.5 – 11.9 4.3 30 4.8

a Initial concentration of indanylmethyl halide = 0.20 M. For QMgX, QH, Q(–H), QOH, and QQ, tabulated values are percentages of Q groups, of the QX consumed, accounted for in the product. No product of ring opening, or any product other than those shown, was found. b Initial concentration, M. c Reaction time, h. d By titration [29]. e By gas chromatography after acidic quenching. QH = methylindane. Q(–H) = methyleneindane. QOH =indanylmethyl alcohol. QQ = bis(indanylmethyl).

Contrary to the model calculation that predicts q= [(QMgX)+(s)]/(RMgX) =3.87, (RMgX)= 20%, (QMgX) =64%, and (s) =16%, no SS or other product of solvent attack s is detected from a Grignard reaction of an o-(3-butenyl)phenyl halide RBr or RI in THF. Acidic quenching gives a very high yield (RH) and a very low yield (QH) (51.5%), with q 50.015 (Table 5). Whether the reaction mixture is quenched immediately or after several hours, the product distribution is the same. RMgX does not ring-close to QMgX under these conditions. This, together with the fact that QMgX does not ring-open, establishes that the yields of RMgX and QMgX are kinetically controlled in THF. Contrary to the model calculation that predicts q = [(QMgX)+ (s)]/(RMgX) =3.59, (RMgX) =22%,

(QMgX)= 73%, and (s) = 5%, no SS or other product of solvent attack s is detected from the Grignard reaction of an o-(3-butenyl)phenyl halide RBr or RI in DEE. Acidic quenching gives a high yield (RH) (] 56%, varying with conditions) and a low yield (QH) (5 25%, varying with conditions), with q5 0.45 (Table 6). Whether the reaction mixture is quenched immediately or after several hours, the product distribution is the same, establishing (with the data of Table 4) yields of RMgX and QMgX are kinetically controlled in DEE. In reactions of o-(3-butenyl)phenyl halides RX in which there is significant cyclization to indanylmethylmagnesium halides QMgX, tetralin Q%H is found (after acidic quenching) as a minor product (identified by GC (co-injection with authentic sample) and GC-MS). The

Table 5 Products of Grignard reactions of o-(3-butenyl)phenyl bromide and iodide (RX) in THF Experiment

X

[MgCl2]0

Model h U95-56 U96-38 U95-57 U95-68 U95-65 U97-82

Br Br Br I I I

0 0 0.50 0 0.50 0.50

b

a

Temperature c

Time d

(TMgBr) e

(RH) f

(QH) f

q

g

37 37 37 37 37 37 67

0.5 1.0 0.5 6.5 6.0 1.0

84 87 82 95 88 96 96

20 106 96 101 98 96 101

64 0.5 0.2 0.1 1.5 1.0 0.04

3.87 0.005 0.002 0.001 0.015 0.010 0.0004

(QQ) f

16 0 0 0 1.1 0 0

a Initial concentration of o-(3-butenyl)phenyl halide = 0.20 M. For TMgX, RH, QH, and QQ, tabulated values are percentages of R groups, of the RX consumed, accounted for in the product. No product other than those shown was found. QD [1-(deuteriomethyl)indane] is formed (1H NMR spectrum) on quenching with D2O, demonstrating the presence of QMgX in the product mixture. b Initial concentration, M. c Temperature, °C. d Reaction time, h. e Total Grignard reagent by titration [29]. T = R+Q. f By gas chromatography after acidic quenching. RH = (3-butenyl)benzene. QH =1-methylindane. The italicized figure for (QQ) is the predicted yield of products of coupling and disproportionation of Q’. RH and QH are assumed to arise from acidic quenching of RMgX and QMgX, respectively, since no traces of SS, reflecting solvent attack, were seen. g Yield ratio [(QMgX)+(s)]/(RMgX). h Model: Eq. (1). See text for details.

J.F. Garst et al. / Inorganica Chimica Acta 296 (1999) 52–66 Table 6 Products of Grignard reactions of o-(3-Butenyl)phenyl bromide and iodide (RX) in DEE Experiment

X

[MgBr2]0

Model h U95-54 U96-36 U95-74 U95-55 U95-64 U95-63 U97-83

Br Br Br Br I I I

0 0 0.13 2.6 0 2.6 2.6

b

59

a

Temperature c

Time d

(TMgBr) e

(RH) f

(QH) f

q

g

37 37 37 37 37 37 37 17

0.5 1.0 0.5 0.5 0.5 1.0 14.0

95 76 75 82 82 65 80 98

22 84 79 80 82 56 90 97

73 16 16 6.0 3.7 25 8.3 5.4

3.59 0.19 0.20 0.075 0.045 0.45 0.092 0.056

(QQ) f

5 1.3 2.3 – – 9.8 2.0 0.4

a

Initial concentration of o-(3-butenyl)phenyl halide = 0.20 M. For TMgX, RH, QH, and QQ, tabulated values are percentages of R groups, of the RX consumed, accounted for in the product. QD [1-(deuteriomethyl)indane] is formed (1H NMR spectrum) on quenching with D2O, demonstrating the presence of QMgX in the product mixture. b Initial concentration, M. c Temperature, °C. d Reaction time, h. e Total Grignard reagent by titration [29]. T = R+Q. f By gas chromatography after acidic quenching. RH = (3-butenyl)benzene. QH =1-methylindane. The italicized figure for (QQ) is the predicted yield of products of coupling and disproportionation of Q’. RH and QH are assumed to arise from acidic quenching of RMgX and QMgX, respectively, since no traces of SS, reflecting solvent attack, were seen. g Yield ratio (QH)/(RH). h Model: Eq. (1). See text for details.

yield is about 5% of that of 1-methylindane, always about 1% or less, and is thus quantitatively insignificant. Since rearrangements of the indanylmethyl radical Q’ are too slow to be significant in these experiments, Q%’ arises from R’ in a reaction that is competitive with its cyclization to Q’.

quenching) (QH)/(RH), are not systematic and probably reflect variations in reaction conditions and analytical methods (small amounts or RH and QH arise in radical disproportionation reactions, and some entries in Table 7 count these along with those from quenching RMgX and QMgX).

4. Discussion

The extents of solvent attack in Grignard reactions of phenyl halides PhX and ring closing in those of o-(3butenyl)phenyl halides RX vary with SH (between THF and DEE), X, and [MgCl2]0 (in THF) or [MgBr2]0 in DEE (Tables 1, 2, 5 and 6). For PhX, there is less solvent attack for THF than DEE, Br than I (in DEE), and 2.6 M MgBr2/DEE than DEE (for Br and I) (Tables 1 and 2). For RX, there is less ring-closure to QMgX for THF than DEE (Tables 5 and 6), for Br than I, and for 2.6 M MgBr2/DEE than DEE (for Br and I). In every case where an effect is observed, THF, Br, and [MgX2]0 \0 give a higher yield of PhMgX or RMgX than DEE, I, and [MgX2]0 = 0 (Tables 1, 2, 5 and 6). The extents of cyclization in Grignard reactions of 5-hexenyl chloride, bromide, and iodide are insensitive to SH (between THF and DEE), X (Cl, Br, I), and [MgX2]0 (MgCl2 in THF, MgBr2 in DEE) (Table 7). The small observed variations in q, (QMgX)/(RMgX) or (after

The dramatic failures (Tables 1, 2, 5 and 6) of predictions based on pathway R (D model) suggest a major pathway X along which R’ is not an intermediate. Alternative explanations are less consistent with the data. The discrepancies between prediction and experiment are unlikely to be due to errors is the values of rate parameters taken for calculations. When reasonable errors are taken into account, the predictions still fail badly. The only alternatives to pathway X are versions of R other than the ideal D model on which the failed predictions are based. (1) The D model does not apply — adsorption of R’ inhibits its reactions. (2) The D model applies but tG is much smaller for aryl radicals than for alkyl radicals. (3) With the usual value of tG, the D model applies, but only to a minor subset of intermediate aryl radicals — for another subset, tG is much smaller. For example, radicals that undergo geminate reactions at the active sites at which they are formed would have very short lifetime, while those that escape geminate reactions would have longer lifetimes. There are experimental facts that militate against each of these alternatives.

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Table 7 Cyclization in Grignard reactions of 5-hexenyl halides (RX) a b

X

SH

Calc g Cl Br Br Br Br Br Br Br I

THF DEE DEE DEE DEE THF DEE THF DEE

[MgBr2]0 c

(RMgX) d

(QMgX) d,e

q

f

0 0 0.18 2.7 0 0 ?h ?h 0

81 g 93 78 73 78 67 90 86 86 27

2.8 g 3.8 3.8 5.5 4.7 1.6 5.0 2.5 2.5 1.1

0.034 g 0.041 0.049 0.075 0.060 0.024 0.056 0.029 0.029 0.042

Reference [7] [7] This work This work This work [7] [7] [30] [30]

a

Temperatures 22–40°C, sometimes with sonication, which does not appear to affect the product distribution. Solvent. c Initial concentration. d Relative yield (%). e Q =cyclopentylmethyl. f (QMgBr)/(RMgBr). g Because c is significant, the infinite-dilution approximation is not very good here. These values are calculated from the equations of the general D model with kP =kI (cyclization of 5-hexenyl) = 4×105 s−1 and tG =3×10−8 s. Values are those of Garst and Swift [5], corrected for a change in yield basis from Mg to RX consumed. h BrCH2CH2Br included in reaction mixture as a promoter. b

(1) Perhaps R is the exclusive pathway but adsorption of R’ inhibits its reactions. The success of the D model for Grignard reactions of a variety of typical alkyl halides and for cyclopropyl bromide opposes this possibility [4,5,10,12]. Since both cyclopropyl and phenyl are s radicals that are exceptionally reactive in atom-transfer reactions, it is unlikely that cyclopropyl is not a good model for phenyl. In addition, Walborsky and Aronoff rejected, for good reasons (see later), the adsorption of R’ as an explanation of partial retention of configuration in Grignard reactions of 1-halo-2,2-diphenylcyclopropanes [31]. They proposed instead that adsorbed radicals racemize and that retention is through a pathway X. If adsorption does not inhibit racemization, then it is not likely to inhibit the ring closure of the o-(2-butenyl)phenyl radical. (2) Perhaps R is the exclusive pathway and the D model applies, but tG is exceptionally small for aryl radicals, much less than the value, 3 × 10 − 8 s that is assumed in the model calculations and that accounts well for product distributions from reactions of 5-hexenyl and cyclopropyl bromides [4,5,10,12]. The fact that tG has the same value for 5-hexenyl and cyclopropyl radicals casts this hypothesis under suspicion by suggesting that tG should have a similar value for aryl radicals. Further, the values of tG that would be required to fit the present data are suspect, at least, and clearly unrealistic in some cases. For reactions of o-(3-butenyl)phenyl bromide and iodide in THF (Table 5), Eq. (1) (q=0.001 – 0.015, kP =5 × 108 s − 1) gives

physically unrealistic values, tG = (2× 10 − 15)–(5× 10 − 13) s, approximately the period of a bond vibration or less. The diffusion equation on which Eq. (1) is based is not valid for such a short time. Even if it did apply, diffusion would be insignificant because the lifetime is so short: the characteristic diffusion distance, (DtG)1/2, would be only 0.02–0.4 A, for a typical value of the diffusion coefficient D, 3× 1011 A, 2 s − 1 (3×10 − 5 cm2 s − 1). Thus, due to its short lifetime, R’ would remain at all times in a position to be reduced. Under these circumstances, perhaps the competition between the R’ reactions leading to RMgX and P should be described by conventional first-order kinetics, Eq. (2) (tG = 1/kG, kG being the first-order rate constant for r), instead of diffusion-reaction kinetics, Eq. (1). q= kPtG

(2)

For q= 0.001–0.015 (Table 5) and kP = 5× 108 s − 1, the values of tG from Eq. (2) are (2× 10 − 12) −(3× 10 − 11) s. These are very short lifetimes, shorter than that (10 − 10 s) of a radical reacting in solution with a 1 M trap at a diffusion-controlled rate (k= 1010 M − 1 s − 1). Such short lifetimes are possible but unlikely. (3) Perhaps R is the exclusive pathway and the D model applies, with tG : 3×10 − 8 s − 1, but only to a subset of intermediate radicals, while another subset has a much shorter lifetime. Geminate reaction and escape (three-dimensional) at a reactive site (*MgZ) could provide these subsets.

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It is not known whether or not there are specific, localized active sites on MgZ in the Grignard reaction, but other information suggests that the geminate reaction hypothesis does not apply here. Observed extents of isomerization (including racemization) in Grignard reactions appear to decrease in the order alkyl \ cyclopropyl\vinyl \aryl [9]. For example, at temperatures of 0°C and above, norbornyl bromides give (nearly) 100% isomerization [6,32], 1-bromo-1methyl-2,2-diphenylcyclopropanes  80% [31], 4methyecyclohexylidenebromoethane (a vinyl bromide) 58% [33], ando-(2-butenyl)phenyl bromide 5 25% (Tables 5 and 6). There is no evident reason why geminate reaction and escape should follow this trend. The obvious and best explanation for the absence of products of reactions of R’ is that R’ is not an intermediate along the major pathway. For Grignard reactions of aryl halides in THF, pathways X and R compete, with X nearly excluding R. Intermediates or transition states along pathway X may resemble RX’−. Since stabilities and lifetimes of RX’− may increase with increasing electron delocalization along the series alkyl Bcyclopropyl Bvinyl Baryl, the observed trend to less radical isomerization along the same series is rational — along this series, pathway X could become more important and pathway R less.

4.1. What is pathway X? In the above scheme, illustrating possible pathways X, the question marks note unknowns. Is there an intermediate along pathway X? If so, does it fragment to give R’? If so, is this the only route to R’? Questions such as these remain without definitive answers, despite the fact that a pathway X was proposed for Grignard reactions of 1-halo-1-methyl-2,2-diphenylcyclopropanes as early as 1973. Different hypotheses accounting for partial retention of configuration in Grignard reactions of 1-halo1-methyl-2,2-diphenylcyclopropanes were put forth by

61

Walborsky and Young (WY) [34] and Walborsky and Aronoff (WA) [31]. That of WY is equivalent to inhibition of racemization by adsorption of R’. WA recognized difficulties in reconciling this with their data and proposed instead a retention pathway X. The A model was first suggested by Kharasch and Reinmuth, who were led to it by by-product yields and ratios [1]. The major by-products of Grignard reactions of alkyl halides are often those of c, rather than s, and even when c is minor, s may not be detected. Kharasch and Reinmuth believed that R’, if it left MgZ and entered the solution, would not survive long enough to undergo significant c and would preferentially suffer s. However, it has been shown that these premises are false [5,10]. Product distributions for Grignard reactions of typical alkyl halides are accounted for very well, quantitatively, by kinetic analyses based on the assumption that R’ diffuses in solution (D model) [5,10]. WY (1964) [34] proposed ‘tight’ and ‘loose’ radicalpair intermediates [R’ ’MgX] in which R’ adheres or does not adhere, respectively, to ’MgX. Coupling of the tight pair gives RMgX with retention and that of the loose pair with racemization. If ’MgX remains at the surface, or is part of it, then the proposed adherence of R’ with ’MgX in the tight radical pair is adsorption of R’ at MgZ. In the loose pair, R’ ‘is sufficiently separated to permit rotation’ and ‘it may become solvent-separated to give a planar’ R’ ‘which could return to the surface of the magnesium.’ Thus, WY allowed for either an A or a D model without envisioning a reaction channel without an intermediate R’ (pathway X). WA (1973) [31] argued for an A model along the lines of Kharasch and Reinmuth (under similar false premises). They replaced the tight radical pair of WY with a ‘tight anion radical cation radical pair’, [RX−’ ’Mg+], that collapses to RMgX. This is a pathway X (no intermediate R’). In keeping with a strict A model, they rejected WY’s idea that [R’ ’MgX] could undergo solvent-separating diffusion in favor of the proposition that adsorbed radicals R’ racemized at MgZ. The mechanisms of WY and WA are compared in Fig. 1. There are good reasons for abandoning adsorption of R’ as a factor in retention of configuration. (1) The possibility that the adsorption of intermediate radicals R’ is responsible for partial retention was rejected by WA because the nature of the halogen strongly affects the extent of racemization (I\Br\ Cl) and RI gives nearly complete racemization. These are logical consequences of competing pathways, not of adsorption of R’.

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WA found less than 2% retention in the Grignard reagent formed from 1-iodo-1-methyl-2,2-diphenylcyclopropane in THF (versus 26% from 1-chloro-1methyl-2,2-diphenylcyclopropane) [31]. Similarly, the reduction by Li0 of 1-fluoro-1-methyl-2,2-diphenylcyclopropane in THF at −3°C gives only 3% retention [35]. If adsorption of R’ were responsible for retention, it would have to be much weaker in these instances than in similar reactions where much more retention is found. There is no evident reason why this should be, nor is there an evident reason why the nature of the halogen should strongly influence the inhibition of racemization by radical adsorption in the observed manner. (2) As noted above, it appears that isomerization (including racemization) varies in the halide order alkyl\ cyclopropyl\ vinyl \aryl, a trend that parallels conjugation (or pseudo-conjugation, in the case of cyclopropyl). Walborsky and Rachon discuss this trend as a consequence of a postulated stronger adsorption of s radicals than p radicals, requiring adsorption of R’ to be a factor in retention, but also contradicting themselves by reaffirming that reactions of adsorbed radicals R’ pair proceed ‘mainly’ or ‘largely’ to racemic product [36]. In this connection, Walborsky put forward a set of three hypotheses: (a) that s radicals are more strongly adsorbed than p; (b) that solvent attack is a reaction of radicals that desorb from MgZ; and (c) that desorbed radicals invariably attack the solvent [3,36]. This set of hypothe-

Fig. 1. The mechanisms of Walborsky and Young [34] and of Walborsky and Aronoff [31]. The first does not include a pathway X and allows the D model. The second includes a pathway X and rejects the D model (in favor of the A model).

ses is directly contradicted by experimental data. These hypotheses predict more solvent attack in Grignard reactions of hexyl (p radical intermediate) than cyclopropyl (s radical) bromide — experiments (including those of Walborsky) show that the reverse is true [12,37]. In addition, if s were more strongly adsorbed than p radicals, the reason is not evident why would there be significant differences in adsorption of such similar s radicals as cyclopropyl and aryl, as the present data would then imply. (3) Partial retention is observed in reductions of 1-bromo-1-methyl-2,2-diphenylcyclopropane in homogeneous solutions [38–40]. Clearly, adsorption of R’ at a surface cannot occur when there is no surface. Therefore, adsorption at a surface is not necessary for retention. Intermediate radicals R’ do not remain adsorbed at MgZ (A model). Instead, they diffuse in solution near MgZ (D model). The evidence supporting the D model is now compelling [4]. According to the A model, deuterating the solvent will have no effect on the yield of RMgX. Indeed, the A-model mechanism of WA predicts that it will have no effect on any aspect of the product distribution. Since desorbing radicals invariably undergo s instead of returning to MgZ (according to WA), they would invariably attack a deuterated solvent also. This is the premise on which Walborsky based his conclusions about the extent of s in Grignard reactions of 1-bromo-1-methyl-2,2-diphenylcyclopropane [31]. This premise is false. For Grignard reactions of cyclopropyl bromide and 1-bromo-1-methyl-2,2-diphenylcyclopropane, A-model predictions are contradicted by observed facts [4,31]. In every case that has been examined adequately, solvent deuteration affects the product distribution from Grignard reactions of cyclopropyl bromide and 1-bromo-1-methyl-2,2-diphenylcyclopropane, and for most media it increases the yield of RMgX significantly. D-model calculations give quantitative accounts of these effects as well as product distributions from Grignard reactions of typical alkyl halides, including those in the presence of radical traps such as dicyclohexylphosphine and TMPO’ (2,2,6,6-tetramethylpiperidine-N-oxyl). The A model is untenable. Pathway R (D model) alone fails to account for retention of configuration in Grignard reactions of cyclopropyl and vinyl halides as well as the present data for Grignard reactions of aryl halides. When rate parameters for D-model calculations are chosen to account for the gross aspects of product distributions (yields of products of r, s, and c), less retention is predicted (ca. 1% for cyclopropyl) than is observed

J.F. Garst et al. / Inorganica Chimica Acta 296 (1999) 52–66

(up to 27% in Grignard reactions of 1-chloro-1-methyl2,2-diphenylcyclopropane). A pathway X is indicated for these cases, as proposed by WA [31]. Although the exact nature of pathway X remains uncertain, it appears to be a dianion pathway, that is, a two-electron reduction of RX in which both electrons are delivered before the R – X bond is broken. This could occur in one step or two (or more).

Any one-step insertion of Mg into the CX bond is described here as a dianion pathway because the formal oxidation numbers in the transition state will be RX − 2Mg + 2. Here the oxidation number of RX is composite (sum of atomic oxidation numbers). In the mechanism of WA [31], pathway X consists of successive one-electron transfer steps with an intermediate anion radical RX’− (as part of a tight pair), a two-step dianion pathway. More recently, Walborsky and Hamdouchi suggested that the ‘tight anion radical cation radical pair’ is a transition state, rather than an intermediate state, making X a one-step dianion pathway [41]. Walborsky and Hamdouchi tried to reconcile several experimental facts and prior theories. They took into account the following. (a) For the reduction of 1bromo-1-methyl-2,2-diphenylcyclopropane in acetonitrile at a glassy carbon electrode, the value of the transfer coefficient a (#DG ‡/#DG 0) is found to be  0.3 [41]. (b) This reduction occurs with 47% retention of configuration [42]. (c) According to Save´ant’s a criteria, a B0.5 implies an initial dissociative electron transfer, giving R’, while a \ 0.5 implies an initial nondissociative electron transfer, giving RX’− [43,44]. (d) According to WA, retention in the Grignard reaction is through a dianion pathway X with an intermediate tight anion radical– cation radical pair [31]. Walborsky and Hamdouchi tried to apply Save´ant’s a criteria and at the same time preserve a dianion pathway X for the Grignard reaction. For the electrode reduction, they accepted Save´ant’s interpretation and proposed a monoanion pathway through an R’ with an extremely short lifetime (to account for partial retention). For the Grignard reaction, they chose instead to modify the tight-pair dianion pathway of Walborsky and Aronoff to keep it from violating the electrochemi-

63

cal conclusion (a criterion) that RX’− is not an intermediate. To do so, they proposed that the tight pair is a transition state, making pathway X a one-step dianion pathway [41]. The question whether X is a one- or two-step dianion pathway cannot be considered to have been resolved. It is not clear why the electrode reduction and the Grignard reaction of the same substrate should have such radically different mechanisms as those proposed by Walborsky and Hamdouchi (a pathway X for the Grignard reaction but not the electrode reduction), despite giving similar products and extents of retention of configuration. If they can have different mechanisms, then it is illogical to apply the a-value for an electrodereduction to reach a conclusion about the Grignard reaction [41]. The result is unsettling too. It is not clear that one-step, two-electron transfer electrode reductions occur, so a special explanation is required for a similar Grignard reaction. Further, if the a-value from the electrode reduction is transferable to the Grignard reaction, then the effect of the proposal of Walborsky and Hamdouchi is that an a-value of 0.3 is compatible with a one-step dianion pathway. This case has not been included in Save´ant’s studies [43,44]. The data can be interpreted in another way. The a criterion is based on energies alone, including those of transition states. No such criterion can be definitive regarding the presence or absence of intermediates. Transition states could have similar energies whether or not there were intermediates (whose energies might be close to those of the similar transition states). Therefore an a-value of 0.3 does not definitively rule out a two-step dianion pathway for the electrode reduction. Both the electrode reduction and the Grignard reaction of 1-bromo-1-methyl-2,2-diphenylcyclopropane could follow competing monoanion and two-step dianion pathways, e.g. pathway R competing with a two-step dianion pathway, as proposed by WA [31]. There are precedents for multi-step dianion pathways in reductions of 1-halo-1-methyl-2,2-diphenylcyclopropanes. For homogeneous-solution chemical reductions of 1-bromo-1-methyl-2,2-diphenylcyclopropane by alkali naphthalenes (M+ Naph− or MNaph), there is substantial, independent evidence of at least one multi-step dianion pathway [38–40]. Like Grignard reactions and electrode reductions, these reactions occur with partial retention of configuration. Since an intermediate R’ would be expected to racemize completely, there must be some other pathway, a conclusion that is further supported by the fact that varying the concentration [MNaph] has no effect on the extent of retention — if the racemization of R’ were competing with its reduction by MNaph, then more retention would be

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found in reactions with higher [MNaph]. Clearly, there is a dianion pathway for which no concentration effect operates. This pathway may be analogous with those that operate in electrode reductions and Grignard reactions. The order of halogen effects is not a reliable indicator of mechanism. For Grignard reactions of 1halo-1-methyl-2,2-diphenylcyclopropanes, retention of configuration decreases in the order Cl \ Br \ I [31], but for their homogeneous-solution reactions with MNaph the order is I\ Br \Cl [39,40]. For reactions of 1-halo-1-methyl-2,2-diphenylcyclopropanes with Li0 the order of the halogen effect on retention is only weakly Cl \Br\ I (63, 45, 36%) in DEE ( 25°C) [31,45] but is Cl\ F (3, 10%) in THF (− 3°C) [35]. Clearly, the order depends on several factors, the balance of which determines any particular case. Therefore we reject as simplistic the argument that variations in directions of halogen effects require completely different mechanisms [3]. By analogy with the proposal of WA for 1-halo-1methyl-2,2-diphenylcyclopropanes [31], pathway X for aryl-halide Grignard reactions could also be a twostep dianion pathway. A problem with this hypothesis arises when the results of studies of analogous electrode reductions are considered. Dianion pathways appear to be without precedent in electrode reductions of aryl halides [43,44]. If Grignard reactions of aryl halides follow such a pathway X, then either (a) electrode reductions and Grignard reactions do not follow parallel mechanisms or (b) the mechanisms of one of these reactions (or both) have been misconstrued. Either is possible. Perhaps a pathway X has been overlooked in studies of electrode reductions of aryl halides. Extensive studies have led to mechanisms in which the initial intermediate is the aryl halide anion radical ArX’− [43,44]. In these mechanisms, the fates of ArX’− are inevitably fragmentation and oxidation, with the latter occurring only where ArX’− is unusually longlived. ArX2 − has neither been proposed as an intermediate nor as a transition state.

This possibility may have been overlooked — it does not appear that a dianion pathway has been ruled out explicitly [43,44]. Thus, it remains possible that both electrode reductions and Grignard reactions proceed through similar mechanisms, competing monoanion and dianion pathways R and X, respectively, in each case. There is some support in the literature for a dian-

ion pathway in an electrode reduction of an aryl halide. When o-(2-butenyl)phenyl bromide in DMF containing D2O is reduced at a Pt electrode, the yield ratio q is 0.2 [17], similar to that found for the Grignard reaction of the same substrate in DEE (Table 6). The low value of q suggests that a pathway X competes with a pathway R. Alternatively, perhaps electrode reductions and Grignard reactions have different mechanisms due to differences in their nature and conditions of reactions. Three substantial differences are obvious. (a) Grignard reactions occur in solvents of low polarity; solvents of higher polarity are usually used for electrode reductions. (b) In Grignard reactions, the positive ions (Mg2 + ) are divalent and small; in electrode reductions, they are monovalent and frequently larger (e.g. tetraalkylammonium). (c) Grignard reactions are metallic corrosions; electrode reductions are not. In solvents of low polarity, such as DEE and THF, and with divalent metal ions, ionic aggregation is much more pronounced than in solvents of higher polarity, such as acetonitrile and DMF, with monovalent cations. The association of ArX’− with Mg2 + could promote the further reduction of ArX’−, relative to its fragmentation of Ar’ and X−, in several ways: (a) it could enhance the lifetime of ArX’− (as limited by fragmentation) by stabilizing the reactant (relative to the fragmentation transition state; (b) it could stabilize the transition state for the reduction of ArX’− (relative to that for fragmentation), or (c) both. Mg(I) species (which are often postulated, but never convincingly demonstrated, as intermediates in Grignard reactions) [9] could have a role here. There is evidence that the oxidation of an Mg0 anode can occur by loss of ’Mg+, which then can reduce a component in solution [46]. Even though this evidence is not compelling (the systems are complex; there are unusual and unexplained observations; the role of the passivating layer of Mg(OH)2 at the surface MgZ is not understood) [47], the fact remains that numerous reductions of solution components have been found to occur at positive Mg electrodes (anodes in electrolytic cells). The transfer of ’Mg+ provides a reasonable explanation. Reduction in the Grignard reaction could occur, at least part of the time, by the transfer of ’Mg+ instead of an electron, e−. The transfer of ’Mg+ to ArX’− would be coulombically favorable for an unassociated ArX’− (unlikely except as a transient) and possibly for an associated one as well. At inert electrodes such as glassy C, no analogous step is possible, so this could explain the operation of a dianion reduction pathway in the Grignard reaction but not in reductions at inert electrodes.

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These results may have practical significance. Several factors appear to influence the partitioning between pathways R and X in reactions of aryl halides but not those of alkyl halides. Since pathway R leads to byproducts but pathway X apparently does not, higher yields of RMgX are expected when the contribution of pathway X is maximized. The data of Table 7 suggest that none of the following factors influence the extent of cyclization in Grignard reactions of 5-hexenyl halides: halogen X (Cl, Br, I), solvent (DEE, THF), added salt (MgBr2). In contrast, each of these factors has a significant effect on the extent of cyclization in Grignard reactions of o-(3butenyl)phenyl halides (Tables 5 and 6) — there is less cyclization in THF than DEE, least with Cl and most with I, and less when MgCl2 is present initially in DEE (and possibly when MgCl2 is present initially in THF). An obvious interpretation is that the contribution of pathway X is maximized (and that of pathway R is minimized) by THF, Cl, and MgX2. The lack of influence of solvent, halogen, and added salt on reactions of 5-hexenyl halides suggests that pathway X is insignificant for these reactions and that the product distribution for pathway R is insensitive to these factors. Other results support the conclusion that Grignard reactions of typical alkyl halides occur primarily, or exclusively, through pathway R [5,8]. In general, the yield of RMgX might be increased by enhancing the contribution of pathway X. Perhaps this accounts for the increased yield that results when the reaction of cyclopropyl bromide is carried out in THF (58%) instead of DEE (52%); 2.6 M MgBr2/DEE (71%) instead of DEE (52%); or 0.5 M MgCl2/THF (68%) instead of THF (58%) [4,48]. In the case of 1-halo-2,2diphenylcyclopropanes, it appears that pathway X is enhanced by lower halogens: RCl \ RBr \ RI [31], just as with o-(2-butenyl)phenyl halides (Tables 5 and 6).

5. Conclusions Aryl radicals R’ are not intermediates along the major pathway for Grignard reactions of aryl halides such as phenyl and o-(3-butenyl)phenyl halides. Instead, the major pathway X is a dianion pathway, along which RX2 − is an intermediate or transition state. X competes with a minor monoanion pathway R, along which R’ is an intermediate. For aryl halides, and perhaps others such as cyclopropyl and vinyl, the contribution of pathway X may be maximized by using THF (instead of DEE), Cl (instead of Br or I), and added salt (MgBr2 or MgCl2). Maximizing the contribution of pathway X also maximizes the yield (RMgX) by minimizing by-product formation. .

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Acknowledgements We are grateful for support through a grant from the National Science Foundation (CHE 9406548).

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