Reactivity of alkenylzirconium complexes toward SH2 substitution By carbon- or heteroatom-centered free radicals

Kevin Kuhn Chemistry Department, Miami University, Oxford, Ohio 45056 Submitted April 23, 2004

Abstract Research has focused on the testing of alkenylzirconium complexes in free radical

(SH2) substitution with sulfur, selenium, and carbon centered radicals. Research goals have included defining the stereo-selectivity and possible mechanisms for the substitution reactions. Good yields of substitution products have been obtained using Sulfur- and Selenium-centered radicals. Preliminary studies using Carbon-centered radicals are promising.

Approval

This Thesis has been approved by:

Dr. James Hershberger ______Advisor

Dr. Richard Taylor ______Reader

Dr. John Grunwell ______Reader

Acknowledgements:

I would like to thank the Miami University USS Program and the Miami University Honors Program for funding. I would also like to thank Dr. James Hershberger for his help and guidance.

Table of Contents Page: Introduction 1 Materials and Methods 3 Results and Discussion 5 Conclusions 10 Experimental 11 References 23

Figures Page: 1 Inhibition Experimentation 7 2 Mass Spectrum of (3,3-Dimethyl-but-1-enylsulfanyl)-benzene 11 3 1H NMR from preparation of (3,3-Dimethyl-but-1-enylsulfanyl)-benzene 11 4 Mass Spectrum of (3,3-Dimethyl-but-1-enylselanyl)-benzene 12 5 1H NMR from preparation of (3,3-Dimethyl-but-1-enylselanyl)-benzene 12 6 1H NMR from preparation of 1-tert-Butylsulfanyl-3,3-dimethyl-but-1-ene 13 7 1H NMR from preparation of 3,3-Dimethyl-1-methylsulfanyl-but-1-ene 14 8 1H NMR from preparation of (3,3-Dimethyl-but-1-enylsulfanylmethyl)-benzene 15 9 Mass spectrum of 1-(3,3-Dimethyl-but-1-enylsulfanyl)-4-methyl-benzene 16 10 1H NMR from preparation of 1-(3,3-Dimethyl-but-1-enylsulfanyl)-4-methyl-benzene 16 11 Mass spectrum of 1-styryl -sulfanyl benzene 17 12 1H NMR from preparation of 1-styryl -sulfanyl benzene 17 13 Gas Chromatograph of (1-Ethyl-but-1-enylsulfanyl)-benzene 18 14 Mass spectrum of (1-Ethyl-but-1-enylsulfanyl)-benzene 18 15 1H NMR from preparation of (1-Ethyl-but-1-enylsulfanyl)-benzene 18 16 1H NMR from preparation of Phenylsulfenyl Chloride 19 17 1H NMR from preparation of (E)-(1-Ethyl-but-1-enylsulfanyl)-benzene 19 18 1H NMR from Isomerization of (E)-(1-Ethyl-but-1-enylsulfanyl)-benzene 20 19 Mass spectrum of 2,2,5-Trimethyl-hex-3-ene 21 20 1H NMR from preparation of 2,2,5-Trimethyl-hex-3-ene 21 21 Mass spectrum of (3-Methyl-but-1-enyl)-benzene 22 22 1H NMR from preparation of (3-Methyl-but-1-enyl)-benzene 22 Illustrations Page:

1 Free radical (SH2) substitution of vinylmetallic compounds 1 2 Reaction pathway one 1 3 Reaction Pathway two 1 4 Chain Propagation 2 5 Possible Mechanisms 2 6 Preparation of (3,3-Dimethyl-but-1-enylsulfanyl)-benzene 5 7 General hetero-atom reaction 5 8 Inhibition Experimentation 6 9 Preparation of (1-Ethyl-but-1-enylsulfanyl)-benzene 7 10 Isomerization of (E)-(1-Ethyl-but-1-enylsulfanyl)-benzene 8 11 Isomer formation 8 12 Preparation of 2,2,5-Trimethyl-hex-3-ene 9

Tables Page: 1 Substitution Products 5 2 Inhibition Experimentation 6

Introduction

Free radical (SH2) substitution of vinylmetallic compounds (ill. 1) has been reported for numerous metals including vinylmercurials [1], vinylplumbanes [2], and vinylstannanes [3].

R H R H R H

X + X +M(L)n

H X H M(L)n H M(L)n 1 (X. = a carbon or heteroatom centered free radical) The mechanism by which vinylmetallics go through free radical substitution must be verified for each individual metal. The previously mentioned metals share a common mechanism in which an intermediate is formed that contains a carbon centered radical bearing a β-metallo substituent. The mechanism suggests that retention of stereochemistry will be lost during this reaction, which is true in many cases. However, it has been shown that in specific cases of vinylstannane and vinylmercurial compounds the reaction can occur with retention [3].

In this report it is shown that many alkenylzirconium complexes do react in SH2 reactions. Work has been done to vary the attacking radical as well as the reactant alkenylzirconium complex in order to report the effects on the reaction. This work was done by applying the following two reaction pathways (ill. 2 and 3). R R' R R' uv light + PhYYPh + Cp2Zr(YPh)Cl

H ZrCp2Cl H YPh 2 R R' R R' uv light + R''Br + Cp2Zr(Br)Cl AIBN H ZrCp2Cl H R'' 3 (Where R, R’, R’’ = alkyl chains or H, Y = S, Se)

1 The chain propagation (ill. 4) of this type of reaction is well known, but the mechanism of the reaction is not known.

ZrCp2Cl + PhYYPh ZrCp2(YPh)Cl + PhS + ZrCp2Cl + RBr ZrCp2BrCl R 4 Therefore, work was also done to test the mechanism of the reaction. As zirconium is the

first transition metal tested in SH2 reaction, it is important to note that the mechanism by which the reaction occurs could be different than the previously studied metals. There are three possible mechanisms by which the free radical reaction could occur (ill. 5).

R R "Zr" R (1) + X +"Zr"

"Zr" X X

R R "Zr" R (2) +"Zr"

"Zr" X X X (3) R

+"Zr"

X 5

(Where “Zr” = Cp2ZrCl) Although this research does not allow a conclusion to be drawn about which mechanism is indeed occurring, initial work on the mechanistic possibilities is presented.

2 Materials and Methods

All 1H NMR spectra were recorded with a Bruker 200 MHz instrument. 13C NMR spectra were recorded with the same instrument at 50 MHz. Mass spectra were obtained via the Varian Saturn 2000 GC-MS equipped with a 30 m glass column packed with fused silica. Hydrozirconation Hydrozirconation is completed to obtain the alkylzirconium complex that is used for further study in each experiment. Zirconocene chloride hydride (Schwartz Reagent) and all alkynes were obtained commercially. A previously described procedure [4] was modified to fit the micro-scale nature of this experimentation. Approximately 50 mg of the Schwartz reagent was dissolved in 0.5 ml benzene-d6 in a 5 mm NMR tube while in an argon atmosphere. The tube was then sealed with a rubber septum. A two-mole equivalent of the appropriate alkyne was then added. The reaction was heated to 45°C and shaken for thirty minutes. Substitutions A slight excess (1.2 mole equivalence) of the appropriate reactant is added through the septum into the hydrozirconation product. Reactants of the form PhYYPh (Y = S, Se) do not require an initiator such as AIBN as they easily form free radicals in UV light. When the reactant is a halogen a 0.25 mole equivalent of AIBN is added to the reaction for the initiation. When a reactant is solid, as is the case with phenyl disulfide, the reactant must first be dissolved in benzene-d6 before addition. After the addition of all necessary reactants, the tube is placed 10 cm from a mercury UV lamp. The reaction is shaken every 5 minutes until the light is removed after 30 minutes. When temperature of the reaction is controlled, the tube is placed in a water jacket flask that is then placed in the light. Preparation of Phenylsulfenyl Chloride Thiophenol, triethylamine, and sulfuryl chloride were purchased commercially. A previously described procedure [5] was modified to one-fourth scale for preparation of the product.

3

Preparation of (E)-(1-Ethyl-but-1-enylsulfanyl)-benzene The hydrozirconation product of 3-hexyne was dissolved in toluene and cooled in acetone/dry ice. A one mole equivalent of phenylsulfenyl chloride was then added to the reaction and stirred for thirty minutes.

4 Results and Discussion

Initial experimentation was completed in order to test the modified procedure for the microscale production of the alkylzirconium complex. 3,3-dimethyl-1-butyne was reacted with the Schwartz reagent and product was obtained. After obtaining the product, the pathway of equation four was tested with phenyl disulfide to create an initial substitution product (ill. 6).

Ph light + SS

Ph S Ph ZrCp2Cl 6 The product was observed with spectral data including 1H NMR, and a mass spectrum. Similar experiments were carried out (ill. 7) and results are presented in tabular form (tab. 1). All products were observed by 1H NMR, and a mass spectroscopy.

R1 R2 R1 R2

+ R3YYR3 + Cp2Zr(YR3)Cl

H ZrCp2Cl H YR3 7 Table 1

R1 R2 R3YYR3 % Yield t-butyl H Phenyl disulfide 84.6 (E) Phenyl t-butyl H diselenide 60.7 (E) t-butyl H t-Butyl disulfide 85.7 (E) t-butyl H Methyl disulfide 50.6 (E) t-butyl H Benzyl disulfide 56.5 (E) t-butyl H p-Tolyl disulfide 81.5 (E) Ph H Phenyl disulfide 65-75 (E) Et Et Phenyl disulfide 69 (E:Z, 2.5:1)

Although the desired products were formed, further study needed to be done to

verify that each was formed via the SH2 pathway. Several experiments were completed to show that the reaction was in fact a photo-induced free radical reaction. Three

5 experiments were completed side-by-side for comparison (ill. 8). The first reaction was used as control and was completed normally. The second reaction was not introduced to light. The third reaction contained 2.5 mol % of Galvonixyl, a free radical scavenger. Galvinoxyl, as a free radical, will inhibit any free radical reaction until it saturated. After saturation of the galvinoxyl, a free radical reaction will then begin to occur.

Ph uv + SS1

Ph S Ph "Zr" 23

no light Galvinoxyl uv

no reaction uv

S Ph 8 The comparative reactions behaved as expected. The reaction did not occur without the presence of light. Galvinoxyl also inhibited the reaction for a short period of time. After saturation, the product in the reaction did begin to form. The reaction completion was measured by comparison of the tert-butyl group of the reactant and product in 1H NMR. Results of this experiment are shown in both tabular (tab. 2) and graphical form (fig. 1). Table 2

UV exposure Tube 1 Tube 2 Tube 3 Control No light Galvinoxyl % Conversion % Conversion % Conversion time (min) 0 0 0 0 2 63.23 0 0 5 64.38 0 0 10 66.49 0 8.81 15 68.33 0 17.87 30 72.58 0 37.01

6 Figure 1

% Conversion Vs. UV Exposure

80 60 Control Reaction 40 2.5 mol% Galvinoxyl 20 No Light 0 % Conversion 0 10203040 uv exposure (min)

As shown in Table 1, the majority of products were obtained in the E- configuration. However, when using 3-hexyne as the initial alkyne, it was shown via gas chromatograph data that both isomers of the product were formed when the reaction was completed (ill. 9).

Ph

"Zr" S Ph light + SS + S

Ph Ph 9 Experimentation was started to determine if both products were being created simultaneously or whether one product was created and later isomerized. Research was planned to test this by running gc-ms after intervals of UV radiation. First, a zero time was completed to make sure that no product would be formed by the extreme heat of gas chromatography. Unfortunately, a small amount of product was formed making the planned experiments invalid. It was shown that the reaction could be initiated by extreme heat.

7 A second approach was then taken to determine the isomerization problem. The authentic (E)-(1-Ethyl-but-1-enylsulfanyl)-benzene was prepared and added to the normal reaction mixture (ill. 10).

Ph Ph

S ZrCp2Cl S PhSSPh + uv + 30 min S

Ph 10 The authentic (E)-(1-Ethyl-but-1-enylsulfanyl)-benzene was rapidly isomerized to give a 60:40 E:Z mixture in the photo-irradiated solution. This mixture ratio is similar to the product ratio obtained in the normal reaction mixture. We conclude that isomerization is faster than substitution. In the case of this post-reaction isomerization, a second radical reacts with the product thereby removing stereochemistry. At that point, one radical is lost and the product can be reformed in both isomers (ill. 11).

R R X R R X

+ X + + X

X X X 11 Because the isomerization happens so quickly, the results of this experiment and the initial product ratio do not help elucidate the mechanism of the reaction. To further the reaction methodology and to help pinpoint the reaction mechanism, experimentation then began with carbon-centered free radicals. This type of free radical substitution, shown in equation 5, has also shown promise. Although unoptimized yields are not high, the products are observed. The desired product from the reaction involving 3,3-dimethyl-1-butyne and 2-bromopropane (ill. 12), was obtained and was observed with 1H NMR. Gas Chromatography was unsuccessful due to the small mass of the product.

8 Br + light AIBN

"Zr" 12 Experimentation was also completed using phenylacetylene and 2-bromopropane. The product was obtained and was observed via 1H NMR, and mass spectroscopy.

9 Conclusions

The results of the preliminary reactions in both pathways show clearly that alkenylzirconium complexes can and do react via free radical substitution. This conclusion is drawn from the photo-induction, and free radical inhibition experiments. Although this work is preliminary, it is possible to list zirconium with the metals that do react in this pathway. With further optimization, it is possible that the alkenylzirconium free radical reaction could become a useful reaction for organic synthesis or other processes. Future work will attempt to elucidate the reaction mechanism. This work will also attempt more variation in carbon-centered radicals and describe trends in reactivity based on chain length, halogen used, and hybridization. More work will also be done to expand and verify the trend shown between the disulfide and diselenide, where disulfide gives a higher yield. Optimization, including functional group tolerance experiments, will be done on all systems that are seen to be synthetically useful, and eventually the reaction will be used in a model synthesis to prove its effectiveness.

10 Experimental Preparation of (3,3-Dimethyl-but-1-enylsulfanyl)-benzene 80 µl (0.66 mmol) tert-Butylacetylene was added to 85 mg (0.33 mmol) Schwartz Reagent in 1ml benzene-d6 in a 5 mm NMR tube sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. 86 mg (0.39 mmol) Phenyl

disulfide was dissolved in 0.5 ml benzene-d6 and added to the reaction. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. 10 µl Methyl benzoate was then added to act as an NMR integration standard. GC-MS (fig. 2) and 1H NMR (fig. 3) were then utilized for product identification.

Based on the integration ratio of the methyl hydrogens in Methyl benzoate at 3.601 ppm to the t-butyl hydrogens of the product at 0.979 ppm, yield of the reaction was 84.6 %.

11 Preparation of (3,3-Dimethyl-but-1-enylselanyl)-benzene 58 µl (0.47 mmol) tert-Butylacetylene was added to 61 mg (0.24 mmol) Schwartz

Reagent in 1ml benzene-d6 in a 5 mm NMR tube sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. 88 mg (0.28 mmol) Phenyl diselenide was dissolved in 0.5 ml benzene-d6 and added to the reaction. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. 10 µl methyl benzoate was then added to act as an NMR integration standard. GC-MS (fig. 4) and 1H NMR (fig. 5) were then utilized for product identification.

Based on the integration ratio of the methyl hydrogens in Methyl benzoate at 3.596 ppm to the t-butyl hydrogens of the product at 0.968 ppm, yield of the reaction was 60.7 %.

12 Preparation of 1-tert-Butylsulfanyl-3,3-dimethyl-but-1-ene 66 µl (0.55 mmol) tert-Butylacetylene was added to 69 mg (0.27 mmol) Schwartz

Reagent in 1ml benzene-d6 in a 5 mm NMR tube sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. 63 µl (0.32 mmol) tert-Butyl disulfide was added to the reaction. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. 10 µl methyl benzoate was then added to act as an NMR integration standard. 1H NMR (fig. 6) was then utilized for product identification.

Based on the integration ratio of the methyl hydrogens in Methyl benzoate at 3.611 ppm to the t-butyl hydrogens of the product at 1.00 ppm, yield of the reaction was 85.7 %.

13 Preparation of 3,3-Dimethyl-1-methylsulfanyl-but-1-ene 66 µl (0.55 mmol) tert-Butylacetylene was added to 70 mg (0.27 mmol) Schwartz

Reagent in 1ml benzene-d6 in a 5 mm NMR tube sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. 48 µl (0.54 mmol) Methyl disulfide was added to the reaction. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. 10 µl methyl benzoate was then added to act as an NMR integration standard. 1H NMR (fig. 7) was then utilized for product identification.

Based on the integration ratio of the methyl hydrogens in Methyl benzoate at 3.59 ppm to the t-butyl hydrogens of the product at 0.984 ppm, yield of the reaction was 50.6 %.

14 Preparation of (3,3-Dimethyl-but-1-enylsulfanylmethyl)-benzene 75 µl (0.61 mmol) tert-Butylacetylene was added to 79 mg (0.31 mmol) Schwartz

Reagent in 1ml benzene-d6 in a 5 mm NMR tube sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. 90 mg (0.37 mmol) Benzyl disulfide was dissolved in 0.5 ml benzene-d6 and added to the reaction. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. 10 µl methyl benzoate was then added to act as an NMR integration standard. 1H NMR (fig. 8) was then utilized for product identification.

Based on the integration ratio of the methyl hydrogens in Methyl benzoate at 3.60 ppm to the t-butyl hydrogens of the product at 1.06 ppm, yield of the reaction was 56.5 %.

15 Preparation of 1-(3,3-Dimethyl-but-1-enylsulfanyl)-4-methyl-benzene 76 µl (0.62 mmol) tert-Butylacetylene was added to 80 mg (0.31 mmol) Schwartz

Reagent in 1ml benzene-d6 in a 5 mm NMR tube sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. 90 mg (0.37 mmol) p-tolyl

disulfide was dissolved in 0.5 ml benzene-d6 and added to the reaction. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. 10 µl methyl benzoate was then added to act as an NMR integration standard. GC-MS (fig. 9) and 1H NMR (fig. 10) were then utilized for product identification.

Based on the integration ratio of the methyl hydrogens in Methyl benzoate at 3.60 ppm to the t-butyl hydrogens of the product at 1.06 ppm, yield of the reaction was 81.5 %.

16 Preparation of 1-styryl -sulfanyl benzene 37 µl (0.34 mmol) phenyl acetylene was added to 44 mg (0.17 mmol) Schwartz

Reagent in 1ml benzene-d6 in a 5 mm NMR tube sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. 45 mg (0.20 mmol) phenyl

disulfide was dissolved in 0.5 ml benzene-d6 and added to the reaction. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. 10 µl methyl benzoate was then added to act as an NMR integration standard. GC-MS (fig. 11) and 1H NMR (fig. 12) were then utilized for product identification.

Due to the lack of easily identifiable peaks in the nmr, yield was estimated by using the relevant peaks in gas chromatography. The yield was estimated to be 65-75%.

17 Preparation of (1-Ethyl-but-1-enylsulfanyl)-benzene 0.24 ml (2.13 mmol) 3-hexyne was added to 0.275 g (1.07 mmol) Schwartz Reagent in 5 ml toluene in a two-headed 25 ml round-bottom flask sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. Solvent and excess reagent was removed by hard vacuum and replaced with fresh toluene. 0.28 g (1.3 mmol) phenyl disulfide was dissolved in 1 ml toluene and added to the reaction. The flask was then placed 10 cm from a mercury UV lamp. The reaction was stirred with a magnetic stir bar until the light was removed after 30 minutes. 10 µl methyl benzoate was then added to act as an NMR integration standard. GC-MS (fig. 13 and 14) and 1H NMR (fig. 15) were then utilized for product identification and E:Z ratio calculations.

The yield of the reaction was 69%, with an E:Z ratio of 2.5:1.

18 Preparation of Phenylsulfenyl Chloride The procedure described by Barrett and Taylor [5] was used in one-quarter scale. 1H NMR (fig. 16) was then utilized for product identification.

Preparation of (E)-(1-Ethyl-but-1-enylsulfanyl)-benzene 0.66 ml (5.8 mmol) 3-hexyne was added to 500 mg (1.9 mmol) Schwartz Reagent in 5 ml toluene in a two-headed 25 ml round-bottom flask sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. Solvent and excess reagent was removed by hard vacuum and replaced with fresh toluene. The flask was then cooled with acetone/dry ice. 22 µl (1.9 mmol) phenylsulfenyl chloride was then added to the reaction and stirred for thirty minutes. 1H NMR (fig. 17) was then utilized for product identification.

19 Isomerization of (E)-(1-Ethyl-but-1-enylsulfanyl)-benzene 0.12 g (0.35 mmol) of the hydrozirconation product of 3-hexyne, 67 mg (0.35 mmol) of (E)-(1-Ethyl-but-1-enylsulfanyl)-benzene and 0.57 mg (0.26 mmol) phenyl disulfide were combined in a 5 mm NMR tube sealed under an argon atmosphere. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. 1H NMR (fig. 18) was then utilized for product identification and for the detection of product isomerization.

20 Preparation of 2,2,5-Trimethyl-hex-3-ene

35 µl (0.29 mmol) tert-butyl acetylene was added to 37 mg (0.14 mmol) Schwartz

Reagent in 1ml benzene-d6 in a 5 mm NMR tube sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. 27 µl (0.29 mmol) 2- bromopropane was added to the reaction. 6 µl (0.04 mmol) AIBN was dissolved in 0.5 ml benzene-d6 and added to the reaction. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. GC-MS (fig. 19) and 1H NMR (fig. 20) were then utilized for product identification.

21 Preparation of (3-Methyl-but-1-enyl)-benzene

43 µl (0.39 mmol) phenyl acetylene was added to 50 mg (0.19 mmol) Schwartz

Reagent in 1ml benzene-d6 in a 5 mm NMR tube sealed under an argon atmosphere. The reaction was heated to 45°C and shaken for thirty minutes. 36 µl (0.39 mmol) 2- bromopropane was added to the reaction. 8 µl (0.05 mmol) AIBN was dissolved in 0.5 ml benzene-d6 and added to the reaction. The tube was then placed 10 cm from a mercury UV lamp. The reaction was shaken every 5 minutes until the light was removed after 30 minutes. GC-MS (fig. 21) and 1H NMR (fig. 22) were then utilized for product identification.

22

References

1. Russell, G.A.; Ros, F.; Mudryk, B. J. Am. Chem. Soc. 1980, 102, 7603-7604. 2. Hershberger, J.; Light II, J.P.; Ridenour, M.; Beard, L. J. Organomet. Chem. 1987, 326, 17-24. 3. Russell, G.A.; Ngoviwatchai, P. Tetrahedron Lett. 1985, 26, 4975-4978. 4. Schwartz, J.; Loots, M.; Kosugi, H. J. Am. Chem. Soc. 1980, 102, 1333-1340. 5. Barrett, G.M., Taylor, Sven. Organic Synthesis, V. 68 pg. 8.

23