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Hoveyda-‐‑Grubbs Second Generation Catalyst for Cross Metathesis of Eugenol with cis-‐‑2-‐‑Butene-‐‑1,4-‐‑diol
Thomas Kelly
Abstract In order to synthesis the natural product (E)-‐‑4-‐‑(4-‐‑Hydroxy-‐‑3-‐‑methoxyphenyl)but-‐‑2-‐‑enol, the starting materials were chosen to be Eugenol and cis-‐‑2-‐‑butene-‐‑1,4-‐‑diol. A cross metathesis reaction was then carried out with a 2nd generation Hoveyda-‐‑Grubbs catalyst. The reaction product was then isolated and purified before characterization using multiple techniques. While due to issues in crystallization, no purified product was isolated for yield calculations, yet the reaction product was confirmed using a variety of techniques.
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Introduction The Metathesis Reaction being investigated here has wide applications within the realm of synthetic organic chemistry. As with any novel tool, new applications and export will be found for the chemistry being illustrated in the following experiment, and therefore I shall leave the potential applications of this work to others such as J.C. Mol1 and merely remark on the breath of potential that metathesis reactions as a whole contain. The 2005 Nobel Prize in Chemistry was awarded to Yves Chauvin, Richard Schrock and Robert Grubbs for their achievements in metathesis mechanics and catalysis. With more than 30 special made catalysts available from Sigma-‐‑Aldrich alone†, the range of chemistry available for synthesis is extensive. This fact is established by the extensive reviews which have been published summarizing a few of the applications of metathesis in Pharmaceutical and Natural Product research2.
In this protocol, Eugenol was reacted with cis-‐‑2-‐‑butene-‐‑1,4-‐‑diol, 1, with an expectation of forming (E)-‐‑4-‐‑(4-‐‑Hydroxy-‐‑3-‐‑methoxyphenyl)but-‐‑2-‐‑enol, 2. Eugenol is a substituted phenyl which was originally isolated from oil of clove3. Compound 1 is a simple unsaturated glycol of butane. Compound 2 is a natural product originally isolated from the root of the Zingiber cassumunar plant and notable for its anti-‐‑inflammatory properties and subsequent medicinal implications4. The primary objective of this experiment was to correctly synthesize and isolate the product and verify its identity as Compound 2.
The catalyst used to run the cross metathesis reaction was a second generation Hoveyda-‐‑Grubbs rubidium complex (Figure 1). This catalyst was prepared a week before the reaction, reference the Experimental Procedure for details.
Experimental Procedure All methods and procedures were followed as
recorded in the Laboratory Manual5. In addition to protocols, observations and qualitative measurements were recorded therein as well. Below is the overall reaction (Figure 2).
† A first order approximation based on general search of reagents available at <http://sigmaaldrich.com/>.
Figure 2. Overall Reaction
Figure 1. Hoveyda-‐Grubbs Catalyst
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Results & Discussion The final, un-‐‑crystalized product mass and the masses of the starting materials were unmeasured and as indicated in the procedure, respectively. The product obtained was in a solvated form which precluded the possibility of recording a final, purified mass; and therefore, there are no yield calculations to present. Although a representatively small sample size, we expect a yield of 2% -‐‑ 5% based data from colleagues‡.
A melting point analysis was planned for the final, purified product, but due to unknown causes, the final product was not isolated. After a week, the end solution was observed to have high clarity and the first signs of a crystalized product. In order to force further product from solution, the mixture was heated and a maximal quantity of the solvent was evaporated to concentrate the compound. Next, the solution was rapidly cooled in an ice bath in the hope of having the purified compound to ‘crash out’ and crystalize. The only observed product was marginal crystallization along the bottom of the flash along with a dark, oily residue.
Thin Layer Chromatography Since an important aspect of synthesis is by providing adequate time for product formation, thin layer chromatography was used to gauge the reaction progress. By blotting the reaction crude product along with the starting material, a qualitative assessment of completion was determined. The reaction was deemed complete once the starting material ‘spot’ had disappeared. Thin Layer Chromatography was also utilized to identify the column fractions which contained the crude product. This was an efficient method for rapidly determining where our product compound was. The presence or absence of the reaction product was clear and obvious, as can be seen in the laboratory notebook. Only the fractions which lacked a Eugenol spot (high, Rf > 0.9, brown spot) and contained a product spot§ were kept and concentrated.
Infrared Spectroscopy As one of three spectrographic techniques used to verify the structure of the reaction product, IR was able to assist primarily in identifying the presence and absence of certain functional groups. Since no IR spec was taken for the reaction product, we are restricted to speaking generally of anticipated results. A significant change in the IR spectrum outside the “fingerprint” region is the new hydroxyl absorption band seen only in the product. Like many
‡ See Table A1 for data and Formula 1a for yield definition. § A green band at Rf ≅ 0.8 as reproduced in the appendix figure A1.
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hydroxyls, the absorption is broad, and it overlaps with the aromatic hydroxyl present in both the product and the starting materials. Since the new hydroxyl on the product is relatively electron poor relative to the phenol, its absorption band is shifted down to lower frequencies.
Nuclear Magnetic Resonance** NMR was utilized in coordination with the other verification methods to determine the carbon structure and placement of functional groups within the purified product. The appearance of two new signals at δ of 3.65 ppm and 4.18 ppm indicate the addition of an alcohol and methylene modality, respectively, to compound 2 relative to Eugenol. One of the characteristics indicative of the transformation from Eugenol to Compound 2 is a relative shift downfield due to the additional electronegative hydroxyl group. This is seen in Spectrum 2 as the ethylene hydrogens are shifted from a δ of 5.00 ppm to 5.60 ppm. This lends support to the successful synthesis of Compound 2.
Mass Spectrometry Mass spectrometry was not conducted since the resulting product was not isolatable. In an attempt to crystalize a purified product out of solution, the mixture was first heated to evaporate the solvent. Once concentrated, the solution was quickly chilled in an effort to have the final compound ‘crash out’, but little to no precipitate was observed. Therefore, we have chosen to present here a representative spectrum in order to describe the features that are expected of Compound 2. The calculated molecular mass of Compound 2 is 193.2 g mol-‐‑1. The mass spectrum indicates a strong peak at 177.1 and 194.1 indicative of a protonated, condensation fragment and the protonated product, respectively. The last peak observed occurs as mass to charge ratio of 212.1: suspected to be an ammonium complex of Compound 2.
Conclusion Although the final, purified product did not crystalize properly, we are confident that our product was the expected: Compound 2. This conclusion was drawn using a variety of source including NMR, IR spectroscopy, Mass spectrometry, and qualitative observations.
** As noted in the Appendix under Spectrum 1 and Spectrum 2, since 1H-‐NMR data was not accessible for the reaction product, calculated spectra have been included instead. Consider this as a tutorial of how results would have been treated instead.
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The unfortunate difficulty in crystallization of the final product precludes the possibility of reaching much of a conclusion; therefore, following are several possible sources of error from the experimental procedure followed. The flash chromatography column is a critical step in the purification of the final product. But as the only columns available with the proper radius were 24” in length, considerable trouble was found when attempting to pack and run such a long column with so little reaction material. Alternatively, an auto-‐‑column would have worked well in running and collecting the proper fractions. Contamination by water or another solvent may have denied the final solution from being able to crystalize. These oversights will be properly addressed for the next experiment.
To end this report with a nod to basic research, provided below is a brief quote by Richard Schrock who was awarded a Nobel in Chemistry for his metathesis research.
“…what we accomplished… came through basic research without really knowing exactly how we were proceeding; we ultimately came to realize, step by step, that our basic research was leading to something really useful. And that is very, very pleasing to me; and I think that’s what the Nobel Prize is all about: to do work that turns out to be useful to society in some way and certainly other fields in science.”6
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Appendices Formula 1a. Yield Calculations Yield, Y, is defined here as the ratio of the product, P, to the starting materials, SM, as measured by number of atoms (or equivalently, in mols).
𝑌 =𝑃𝑆𝑀 ≡
[𝑚𝑜𝑙]![𝑚𝑜𝑙]!"
Formula 1b. Yield calculation from Mass In order to calculate Yield based on weights the following equation was used where mass and molar mass are m and M, respectively.
𝑌 =𝑚!
𝑚!"
𝑀!"
𝑀!
Example: Consider the following reaction where 2.0 g of benzene is sulfonated to form 1.9 g of product.
𝐵𝑒𝑛𝑧𝑒𝑛𝑒 !!!!! 𝐵𝑒𝑛𝑧𝑒𝑛𝑒𝑠𝑢𝑙𝑓𝑜𝑛𝑖𝑐 𝐴𝑐𝑖𝑑
Therefore;
𝑌 =1.9 𝑔2.0 𝑔
78.1 𝑔/𝑚𝑜𝑙158 𝑔/𝑚𝑜𝑙 = 47 %
Table A1. Collaboration Data Peers working in other groups provided this data. Since their protocols are similar to ours, we are confident that their results are indicative of a probable outcome for our product.
Group Yield Melting Pt. (oC)
1 (AJA) 2.47% 93.5-‐‑96.5 2 (DH) 4.81% 88.5-‐‑94.0
Table A2. Compound Data
Compound Molecular Mass Eugenol 164.2
Compound 1 88.1 Compound 2 193.2
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Spectrum 1. Eugenol 1H-‐‑NMR Provided below is a calculated spectrum for Eugenol as a means of comparison between the starting material and product. The spectrum was calculated using ChemBioDraw Ultra version 12.0.3.1216 by CambridgeSoft.
Spectrum 2. Compound 2 1H-‐‑NMR Provided below is the theoretical spectrum for the expected product, Compound 2. The spectrum was calculated using ChemBioDraw Ultra version 12.0.3.1216 by CambridgeSoft.
ChemNMR 1H Estimation
6.72
6.62
6.84
5.35
3.83
3.21
5.92
5.00
4.98
OH
O
H
H
H
Estimation quality is indicated by color: good, medium, rough
01234567PPM
Protocol of the H-1 NMR Prediction:
Node Shift Base + Inc. Comment (ppm rel. to TMS)
OH 5.35 5.00 aromatic C-OH 0.35 general correctionsCH 6.84 7.26 1-benzene -0.49 1 -O-C -0.17 1 -O -0.20 1 -C 0.44 general correctionsCH 6.72 7.26 1-benzene -0.11 1 -O-C -0.53 1 -O -0.12 1 -C 0.22 general correctionsCH 6.62 7.26 1-benzene -0.44 1 -O-C -0.17 1 -O -0.20 1 -C 0.17 general correctionsCH3 3.83 0.86 methyl 2.87 1 alpha -O-1:C*C*C*C*C*C*1 0.10 general correctionsCH2 3.21 1.37 methylene 1.22 1 alpha -1:C*C*C*C*C*C*1 0.63 1 alpha -C=C -0.01 general correctionsH 5.92 5.25 1-ethylene 1.05 1 -C-1:C*C*C*C*C*C*1 gem -0.38 general correctionsH 5.00 5.25 1-ethylene -0.29 1 -C-1:C*C*C*C*C*C*1 cis 0.04 general correctionsH 4.98 5.25 1-ethylene -0.32 1 -C-1:C*C*C*C*C*C*1 trans 0.05 general corrections
1H NMR Coupling Constant Prediction
shift atom index coupling partner, constant and vector
5.35! 76.84! 6! 4! 1.5!!H-C*C*C-H6.72! 3! 4! 7.5!!H-C*C-H6.62! 4! 3! 7.5!!H-C*C-H! 6! 1.5!!H-C*C*C-H3.83! 93.21! 10! 13! 6.2!!H-CH-C(sp2)-H! 14! -1.0!!H-CH>CH=CH<H! 15! -1.0!!H-CH>CH=CH>H5.92! 13! 10! 6.2!!H-C(sp2)-CH-H! 14! 16.8!!H>C=CH>H! 15! 10.0!!H>C=CH<H5.00! 14! 15! 2.1!!H-C(sp2)-H! 13! 16.8!!H>CH=C>H! 10! -1.0!!H>CH=CH<CH-H4.98! 15! 14! 2.1!!H-C(sp2)-H! 13! 10.0!!H>CH=C<H! 10! -1.0!!H>CH=CH>CH-H
Spectrum 1. Eugenol 1H-‐NMR.
ChemNMR 1H Estimation
6.72
6.62
6.84
5.35
3.83
3.21
4.18
3.65
5.60
6.29OH
OOH
H
H
Estimation quality is indicated by color: good, medium, rough
01234567PPM
Protocol of the H-1 NMR Prediction:
Node Shift Base + Inc. Comment (ppm rel. to TMS)
OH 5.35 5.00 aromatic C-OH 0.35 general correctionsOH 3.65 2.00 alcohol 1.65 general correctionsCH 6.84 7.26 1-benzene -0.49 1 -O-C -0.17 1 -O -0.20 1 -C 0.44 general correctionsCH 6.72 7.26 1-benzene -0.11 1 -O-C -0.53 1 -O -0.12 1 -C 0.22 general correctionsCH 6.62 7.26 1-benzene -0.44 1 -O-C -0.17 1 -O -0.20 1 -C 0.17 general correctionsCH2 4.18 1.37 methylene 0.63 1 alpha -C=C 2.20 1 alpha -O -0.02 general correctionsCH3 3.83 0.86 methyl 2.87 1 alpha -O-1:C*C*C*C*C*C*1 0.10 general correctionsCH2 3.21 1.37 methylene 1.22 1 alpha -1:C*C*C*C*C*C*1 0.63 1 alpha -C=C -0.01 general correctionsH 5.60 5.25 1-ethylene 0.64 1 -C-O gem -0.29 1 -C-1:C*C*C*C*C*C*1 cisH 6.29 5.25 1-ethylene -0.01 1 -C-O cis 1.05 1 -C-1:C*C*C*C*C*C*1 gem
1H NMR Coupling Constant Prediction
shift atom index coupling partner, constant and vector
5.35! 73.65! 146.84! 6! 4! 1.5!!H-C*C*C-H6.72! 3! 4! 7.5!!H-C*C-H6.62! 4! 3! 7.5!!H-C*C-H! 6! 1.5!!H-C*C*C-H4.18! 13! 15! 6.2!!H-CH-C(sp2)-H! 16! -1.0!!H-CH>CH=C<H3.83! 93.21! 10! 16! 6.2!!H-CH-C(sp2)-H! 15! -1.0!!H-CH>CH=C<H5.60! 15! 13! 6.2!!H-C(sp2)-CH-H! 16! 15.1!!H>C=C>H! 10! -1.0!!H>C=CH<CH-H6.29! 16! 10! 6.2!!H-C(sp2)-CH-H! 15! 15.1!!H>C=C>H! 13! -1.0!!H>C=CH<CH-H
Spectrum 2. Compound 2 1H-‐NMR.
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Figure A1-‐‑ TLC band of Product This band was used to determine which of the column fractions to keep. All fractions showing this band were collected and the product was purified from them.
Rf = 0.80
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References 1 Mol J.C. Industrial Applications of Olefin Metathesis. Journal of Molecular Catalysis
A: Chemical 213, 39-‐45. (2009). 2 Pederson R. The Efficient Application of Metathesis in Pharmaceuticals and Fine
Chemicals. Fine Chemicals R&D. (Unpublished). <http://www.isom17.com/summaries/Pederson,%20Richard-‐ISOM%20XVII.pdf>
3 Jadhav et al. Formulated and Evaluation of Mucoadhesive Tablets Containing Eugenol for the Treatment of Periodontal Diseases. Drug Development and Industrial Pharmacy 30.2, 195-‐203. (2004).
4 Taber D., Frankowski K., Grubbs’s Cross Metathesis of Eugenol with cis-‐2-‐Butene-‐1,4-‐diol To Make a Natural Product. Journal of Chemical Education 83.2, 283-‐284. (2006).
5 Kelly T. Laboratory Notebook. Unpublished. 6 Casey C. 2005 Nobel Prize in Chemistry. Journal of Chemical Education. 83.2, 192-‐
195. (2006).
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