Rep:Mod:EXPT1C3614

Part1:The Hydrogenation of Cyclopentadiene Dimer

Dimerisation of Cylcopentadiene

Introduction

At room temperature, cyclopentadiene tends to dimerise through [4+2] cycloaddition. Specifically, endo dimer 2 is formed instead of exo dimer 1. In order to determine whether the dimerisation is kinetically or thermodynamically controlled, Avogadro was used to calculate the energies of both dimer products (1 and 2). The geometries of the dimers were optimised using the MMFF94(s) force field with conjugate gradients.

Results and Discussions

Based on the energies showed in the table below, the endo dimer 2 has slightly higher energy than exo dimer 1. This indicated that endo dimer 2 is kinetic product whereas the endo dimer is thermodynamic product. As endo dimer 2 is preferential formed, cylcodimerisation of cyclopentadiene is kinetically controlled. It also indicated that the transition state proceed to the endo dimer 2 is lower energy than the exo dimer 1, so it acts as a point of no return in the reaction. Moreover, the angle bending energy and electrostatic energy are the most contribution to the difference in energy of the two dimmers.

Table 1: Energies and Structures of Endo and Exo Cyclopentadiene Dimer

	EXO DIMER 1	ENDO DIMER 2
STRUCTURE	Vibration	Vibration
TOTAL BOND STRETCHING ENERGY (kcal/mol)	3.54308	3.46781
TOTAL ANGLE BENDING ENERGY (kcal/mol)	30.77256	33.18935
TOTAL STRETCH BENDING ENERGY (kcal/mol)	-2.04140	-2.08217
TOTAL TORSIONAL ENERGY (kcal/mol)	-2.73064	-2.94953
TOTAL OUT-OF-PLANE BENDING ENERGY (kcal/mol)	0.01476	0.02183
TOTAL VAN DER WAALS ENERGY (kcal/mol)	12.80139	12.35879
TOTAL ELECTROSTATIC ENERGY (kcal/mol)	13.01367	14.18457
TOTAL ENERGY (kcal/mol)	55.37342	58.19067

Part 1:Hydrogenation of Cylcopentadiene Dimer

Introduction

Upon the hydrogenation of the endo dimer 2 above, one of the dihydro derivatives 3 or 4 is formed initially by hydrogenating one of the double bonds. Only after prolonged period, both of the double bonds are hydrogenated and form a tetrahydro derivative. Avogadro was used again to calculate the energies of both dihydro derivatives and their geometries optimised using the MMFF94(s) force field with conjugate gradients. This enabled the relative ease of hydrogenation of each of the double bonds to be determined.

Results and Discussions

From the table below, dihydro derivative 3 has a lower energy than the derivative 4. If the hygenation of the dimer is under thermodynamic controlled, the double bond in the norbornene is hydrogenated faster than the double bond in the cylcopentane ring. This is true indeed, from the work of D. Skala and J.Hanika (Use of powdered palladium as the catalyst) , the hydrogenation of the double bond in the norbornene was five time faster, hence derivative 4 is the preferred product to be formed. Moreover, the relative stability of derivatives 3 and 4 can be accounted in different energy terms. Apart from the total electrostatic energy and total stretch bending energy, the derivative 4 generally has a lower value than derivative 3 in the remained energy contributions. Especially, the total angle bending energy and total van der waals energy are the most contribution towards the lower stability of the derivative 3.

Table 2: Energies and Structures of Compound 3 and 4 (Hydrogenated products)

	COMPOUND 3	COMPOUND 4
STRUCTURE	Vibration	Vibration
TOTAL BOND STRETCHING ENERGY (kcal/mol)	3.30683	2.82309
TOTAL ANGLE BENDING ENERGY (kcal/mol)	30.85252	24.68548
TOTAL STRETCH BENDING ENERGY (kcal/mol)	-1.92610	-1.65720
TOTAL TORSIONAL ENERGY (kcal/mol)	0.07843	-0.37846
TOTAL OUT-OF-PLANE BENDING ENERGY (kcal/mol)	0.01517	0.00028
TOTAL VAN DER WAALS ENERGY (kcal/mol)	13.27502	10.63729
TOTAL ELECTROSTATIC ENERGY (kcal/mol)	5.12096	5.14702
TOTAL ENERGY (kcal/mol)	50.72283	41.25749

Part 1: Atropisomerism in an Intermediate related to the Synthesis of Taxol

Introduction

Intermediate 9 or 10 are the key part of taxol (used in chemotherapy for ovarian cancers) synthesis. They are atropisomers to each other and the main difference is the C=O bond pointing either up or down. The barrier of bond rotation within these two intermediates enables them to be isolated separately. They both are synthesised from an oxy-Cope rearrangement and their stability was investigated by using Avogadro with the MMFF94(s) force field.

Results and Discussions

For both intermediates, the position of the H in trans alkene and the fused cyclohexane ring are important factors in minimising the energy of the structure. The most stable conformation of the cyclohexane ring is known to be chair and the second stable conformation is boat. For the intermediates 9 and 10, the fused cyclohexane ring is able to adopt three different conformations (two chairs and 1 slightly twisted boat form, see below). As expected, the lowest energy structure of the intermediate contains chair conformation in the cyclohexane ring (see in the optimised structures). The H in trans alkene can either pointing up or down in the plane of the 11-member ring, but it needs to be pointing up for achieving lowest energy structure for both intermediates. After both intermediate get optimised, it was found out that intermediate 10 is more stable (9.98 kcal / mol lower in energy). It can be said that upon carbonyl addition, the stereochemistry of the product is dependent on the structure of intermediate 10 rather than intermediate 9.

Unlike most of the bridgehead olefin being unstable due to large olefin strain, the double bond within both intermediates was observed to be reacted slowly, i.e. in hydrogenation. This inertness can be accounted by the fact that the bridgehead double bond is part of a large polycyclic system . From calculation (see table below), the intermediates have a lower total energy than their corresponding parent hydrocarbons, so a lower strain is associated within their structures, hence they are much more stable. This stability makes the intermediates become unusually unreactive.

Table 3:Energies and Structures of the optimised structure of Intermediates 9 and 10 and their corresponding parent hydrocarbon

	Intermediate 9	Intermediate 10	Parent Hydrocarbon of 9	Parent Hydrocarbon of 10
STRUCTURE	Vibration	Vibration	Vibration	Vibration
TOTAL BOND STRETCHING ENERGY (kcal/mol)	7.66872	7.58585	6.95858	6.62300
TOTAL ANGLE BENDING ENERGY (kcal/mol)	28.26377	18.79974	28.75155	24.74986
TOTAL STRETCH BENDING ENERGY (kcal/mol)	-0.08084	-0.13762	0.26695	0.43617
TOTAL TORSIONAL ENERGY (kcal/mol)	0.26954	0.19437	10.59478	8.29638
TOTAL OUT-OF-PLANE BENDING ENERGY (kcal/mol)	0.97514	0.84178	0.10699	0.06959
TOTAL VAN DER WAALS ENERGY (kcal/mol)	33.14278	33.32951	33.15969	31.29288
TOTAL ELECTROSTATIC ENERGY (kcal/mol)	0.30157	-0.05560	0.00000	0.00000
TOTAL ENERGY (kcal/mol)	70.54069	60.55804	79.83855	71.46789

Table 4:Possible structures of Intermediates 9 and 10 but with higher energy than optimised one

	Intermediate 9	Intermediate 9	Intermediate 9	Intermediate 10	Intermediate 10	Intermediate 10
Structure	Another Chair form	Slightly twisted boat form	Optimised form but with trans H pointing down	Another Chair form	Slightly twisted boat form	Optimised form but with trans H pointing down
Total Energy (kcal/mol)	82.66931	88.45613	77.65100	75.02768	66.32301	61.03065

Part 1:Spectroscopic Simulation using Quantum Mechanics

Introduction

The molecules 17 and 18 are derivative of 9 and 10 above, they are also atropisomers due to formation from the oxyanionic Cope process. Same as before, MMFF94s mechanics forces field in the Avogadro program was used in the first stage of the optimisation of molecules 17 and 18.

Results and Discussions

As they adopt similar structure as 9 and 10, any adjustments that optimising the structure of 9 and 10 can be applied to molecules 17 and 18 as well. Therefore in minimising the energies of both molecules, the fused cyclohexane ring was adjusted into chair form. However, the cyclohexane ring can adopt two different chair forms and the resulted conformations had a difference in total energy. Indeed the conformations with smallest total energy are the optimised structure of 17 and 18, which are shown in the table below. (click links here to see the higher energies chair conformation : Molecule 17 with 131.64330 kcal/mol and Molecule 18 with 106.05637 kcal/mol).

Table 5: Optimised Structures of Natural occurring Molecule 17 and 18

	Molecule 17	Molecule 18
Structure	Vibration	Vibration
Total energy (kcal/mol)	104.36629	100.52704

Molecule 17 was chosen to investigate further. It’s 1H and 13C NMR spectra were stimulated by using the Gaussian and HPC calculations (using Theory: B3LYP, Basis: 6-31G(d,p), Solvation model: SCRF(CPCM, Solvent = chloroform), Freq and NMR as key word and Empirical Dispersion : GD3 ). The obtained NMR data was indicated in the table below, it was compared directly to the literature values by plotting them in the same graph. In the 1H NMR data, the data matched quite well in the chemical shift from 3.5 - 5ppm, but with an observable deviation at lower chemical shift value (< 3.5 ppm). This is mainly arise from the assumption that used in the plotting the literature data. The literature reported a multiplet of 14H in the chemical shift range of 1.35-2.80, it was assumed that the 14H are equally distributed in the chemical shift range in the plotting of the graph. However, it is known that this assumption cannot reflect the true picture of the multiplet, so deviations were resulted. In the 13 C data, a better match was observed and this is because all 20 carbon signals were explicitly reported in the literature, no assumption need to make as in the 1H data. For both 1H and 13C NMR spectra, the graphs reflected that the literature value and the calculated values were in a good match although with small deviations. Therefore, it can be said that the literature values are correctly interpreted and assigned. The other possible origin of the small deviations can come from the sensitivity and precision of NMR instrument that used in the literature and the one accounted in the calculation,heavy atom effect of the two sulfur atom, as well as the temperature and pressure during the measurement.

Table 6: Comparison of 1H NMR data of Molecule 17 between HPC calaculation and Literature value DOI:10042/27337

Calculated Data	Literature Value	Comparison
	1H NMR (300 MHz, CDCl3) ppm 4.84 (dd, J = 7.2,4.7 Hz, 1 H) ,3.40-3.10 (m ,4H), 2.99 ( dd, J = 6.8, 5.2 Hz, 1 H), 2.80-1.35 (series of m, 14 H), 1.38 (s, 3 H), 1.25 (s, 3 H), 1.10 (s, 3 H), 1.00-0.80 (m, 1 H)

Table 7: Comparison of 13C NMR data of Molecule 17 between HPC calaculation and Literature value DOI:10042/27337

Calculated Data	Literature Value	Comparison
	13C NMR (75 MHz, CDCL3) ppm 218.79, 144.63, 125.33, 72.88, 56.19, 52.52,48.50, 46.80, 45.76, 39.80,38.81, 35.85, 32.66, 28.79, 28.29, 26.88, 25.66, 23.86, 20.96, 18.71

Table 8: Stimulated NMR specturm of Molecule 17 DOI:10042/27337

1H NMR	13C NMR
SVG	SVG

In addition, the HPC calculation enabled vibrational analysis of the molecule 17 and 18 to be reported. The entropy and zero-point-energy correction were computed to give a Gibbs free energy (∆G), see in the table 9. Molecule 18 has a more negative value of the free energy than molecule 17, so it indicates that molecule 18 is the prefer conformation to be formed upon synthesis. Combining the fact that molecule 18 was found out to be the lower energy conformation, molecule 18 is the most thermodynamically stable conformation and transformation from molecule 17 to molecule 18 is feasible. In order for the transformation to happen, energy input (e.g. reflux) is required for the rearrangement of structure, which involves several sigma-bond rotations and turning the carbonyl oxygen to point down. Despite of a lower energy is attained in this conformation, the methyl that is alpha to the carbonyl was required to be brought closer to the methyl group in the bridgehead ( from 0.571nm to 0.385 nm).

Table 9: Vibrational Analysis of Molecule 17 and 18

Hartree/Particle	Molecule 17 DOI:10042/27337	Molecule 18 DOI:10042/27336
Zero-point correction	0.467966	0.467822
Thermal correction to Energy	0.489479	0.489247
Thermal correction to Enthalpy	0.490423	0.490191
Thermal correction to Gibbs Free Energy	0.420580	0.421084
Sum of electronic and zero-point Energies(E0 = Elec + ZPE)	-1651.412064	-1651.416521
Sum of electronic and thermal Energies (E=E0+Evib+Erot+Etrans)	-1651.3905	-1651.395096
Sum of electronic and thermal Enthalpies(H=E+RT)	-1651.389607	-1651.4152
Sum of electronic and thermal Free Energies (free energies) (G=H-TS)	-1651. 459451	-1651.463259

Part 2 Analysis of the properties of the synthesised alkene epoxide

Crystallised Structure of the Shi catalyst and the Jacobsen eopoxide catalyst

The crystal structure of the Shi and Jacobsen pre catalysts were obtained from the Cambridge crystal database using the Conquest program. Shi pre catalysts 21 (NELQEA) and Jacobsen pre catalyst 23 (TOVNIB 02).

Results and Discussions

There are total four anomeric centres within the structure of pre catalyst 21. Only several C-O bonds are shorter than the normal C-O bond, 0.142 nm (sum of the covalent radii of oxygen and carbon). These are because of the anomeric effect, the lone pair of the oxygen atom is donated to the sigma * C-O orbital adjacent, which in turn shorten the C-O bond. Whether the C-O bond get shorten or not is dependent on the direction of the inductive effect of the carbonyl group. As shown in the crystallised structure and the diagram below, there have four shorter C-O bonds in the pre catalyst 21.

Table:10 Crystal structure of Shi pre-catalyst 21

Vibration

Atom C-O bond length/nm O5-C28 0.1409 O4-C28 0.1439 O6-C10 0.1403 O7-C10 0.1403 O7-C1 0.1441 O19-C1 0.1413

For the Jacobsen pre catalyst 23, the Mn metal centre is coordinated to five different ligands. From the crystal structure below, it indicated that it adopts the square based bipyrimidal structure instead of the common trigonal bipyrimdal structure. with the Cl located in the axial position. This can be due to the fact that all ligands (apart from the Cl) are part of a ring, and the unfavourable torsional strain will be avoided if they are all located in the equatorial position and force the Cl atom in the axial position. In contrast, the torsional strain will be presented in the trigonal bipyrimidal structure, so it becomes higher in energy conformation, hence it is not adopted by the pre catalyst 23. And also, in the adjacent t-butyl group, there are several H…H short attractive interactions observed (0.26-0.33 nm, when maximum attraction is generally achieved at 0.24 nm), therefore this lowers the energy of the conformation even further. Moreover, the cyclohexane ring of the equatorial ligand prefers to adopt a lower energy chair conformation. This results that two CN bond are not located in the same plane, one slightly pointing up while the other one slightly point down.

Table:11 Crystal structure of Jacobsen pre-catalyst 23

Vibration

Calculated NMR properties of the Epoxide

Introduction

Trans-Stilbene (Alkene 3) and 1,2-dihydronaphthalene (Alkene 4) were selected specifically in the following investigation.

Same methods as Molecule 17 and 18 were used in obtaining the optimised structure of the epoxides and their associated NMR spectrums, which are shown in table below. Epoxidation is a stereospecific reaction, so the cis /trans geometries of the alkene reactants can be retained in the structure of the epoxide product. However, it is proceed via a syn addition mechanism, so the enantiomerism can be arise in the epoxide product. As a result, analystical techniques are needed to determine the absolute configuration of the epoxide. Upon the epoxidation, tran stilbene (Alkene 3) forms a pair of enantiomer (RR&SS) for both Shi and Jacobsen catalyst , whereas 1,2-dihydronaphthalene (Alkene 4) forms two pair of enatiomers (RS&SR) with Shi catalyst and (RR&SS) with Shi and Jacobsen catalyst

Results and Discussions

Table:12 Structure of Epoxides and their energies

	Epoxide 3 RR	Epoxide 3 SS	Epoxide 4 1R,2S	Epoxide 4 1S,2R	Epoxide 4 1R,2R	Epoxide 4 1S,2S
Structure	Vibration	Vibration	Vibration	Vibration	Vibration	Vibration
Total energy (kcal/mol)	39.45758	39.45707	30.22441	30.68361	68.09584	68.09672

It can be seen from the table below that the epoxide has a very similar calculated 13C and 1H NMR spectrums within a same pair of enantiomer. Therefore, NMR cannot be a good tool in determining the absolute configuration of the epoxide.

Table:13 NMR spectrums of the Epoxides

Epoxide 3 RR 13C spectrum DOI:10042/27335	Epoxide 3 RR 1H spectrum DOI:10042/27335	Epoxide 3 SS 13C spectrum DOI:10042/27334	Epoxide 3 SS 1H spectrum DOI:10042/27334
SVG	SVG	SVG	SVG
Epoxide 4 1R,2S 13C spectrum DOI:10042/27332	Epoxide 4 1R,2S 1H spectrum DOI:10042/27332	Epoxide 4 1S,2R 13C spectrum DOI:10042/27331	Epoxide 4 1S,2R 1H spectrum DOI:10042/27331
SVG	SVG	SVG	SVG
Epoxide 4 1R,2R 13C spectrum DOI:10042/27330	Epoxide 4 1R,2R 1H spectrum DOI:10042/27330	Epoxide 4 1S,2S 13C spectrum DOI:10042/27333	Epoxide 4 1S,2S 1H spectrum DOI:10042/27333
SVG	SVG	SVG	SVG

The calculated chiroptical properties of the product

Optical Rotation Power (ORP)

On the other hand, optical rotatory power (ORP) can be a good indicator in the absolute configuration of the molecule. It can be easily measured in the laboratory, as well as it can be generated from the calculations. First, the ORP of all the enantiomers of the epoxides were obtained by searching on the Reaxy. Unfortunately, the ORP of Epoxide 4 RR and SS cannot be found. In the same time, the ORP were calculated based on the optimised structure of the corresponding epoxides. It was involved the use of theory of B3LYP, basis set of 6-31G (d,p) and chloroform as a solvent and at wavelength of 589nm and 365 nm. The comparisons of both results were listed in the table below.

The measured and literature ORP were in a good matched for epoxide 3, only with a small deviation. However, significant deviations were observed for epoxide 4 (RS and SR). Because of the literature value of epoxide (RR and SS) could not be found, so no comparison between them. It can be concluded that calculations used in ORP is reliable for the absolute configuration of the epoxide 3 and they are assigned correctly in the literature. For epoxide 4, due to insufficient information, it is hard to say whether the calculation method is reliable or not. If more time was given, calculation of the epoxide 4 will be repeated and the literature ORP of epoxide 4 RR and SS will be searched again in other online chemical database, instead of Reaxys.

Table:14 Comparison of calculated ORP of the Epoxide 3 with its literature values

	Literature Epoxide	Calculated Epoxide 3 RR DOI:10042/27317		Literature Epoxide 3 SS	Calculated Epoxide 3 SS DOI:10042/27318
Condition	0.80 g/100ml , 93% ee, benzene,589 nm, 25 degree celsius	CAM-B3LYP/6-311++g(2df,p) polar(optrot) scrf(cpcm,solvent=chloroform) CPHF=RdFreq		0.56 g/100ml, 89 %ee, chloroform, 589 nm, 15 degree celsius	CAM-B3LYP/6-311++g(2df,p) polar(optrot) scrf(cpcm,solvent=chloroform) CPHF=RdFreq
Rotation [Aplha]	319.8 deg	297.73 deg		-205.2 deg	-297.81 deg

Table: 15 Comparison of calculated ORP of the Epoxide 4 with its literature values

	Literature Epoxide 4 1R,2S	Calculated Epoxide 4 1R,2S DOI:10042/27316		Literature Epoxide 4 1S,2R	Calculated Epoxide 4 1S,2R DOI:10042/27318
Condition	0.81 g/100ml , CHCl3,589 nm, 20 degree celsius	CAM-B3LYP/6-311++g(2df,p) polar(optrot) scrf(cpcm,solvent=chloroform) CPHF=RdFreq		0.2 g/100ml , 97 %ee, Chloroform,589 nm, 25 degree celsius	CAM-B3LYP/6-311++g(2df,p) polar(optrot) scrf(cpcm,solvent=chloroform) CPHF=RdFreq
Rotation [Aplha]	129 deg	-35.86 deg		-90.5 deg	-155.82 deg
	Literature Epoxide 4 1R,2R	Calculated Epoxide 4 1R,2R DOI:10042/27311		Literature Epoxide 4 1S,2S	Calculated Epoxide 4 1S,2S DOI:10042/27314
Condition	cannot be found	CAM-B3LYP/6-311++g(2df,p) polar(optrot) scrf(cpcm,solvent=chloroform) CPHF=RdFreq		cannot be found	CAM-B3LYP/6-311++g(2df,p) polar(optrot) scrf(cpcm,solvent=chloroform) CPHF=RdFreq
Rotation [Aplha]	cannot be found	-246.61 deg		cannot be found	246.61 deg

Electronic Circular Dichroism (ECD)

VCD and ECD are feasible as well in the determination of the absolute configuration of compound. For ECD (UV spectrum recorded with polarised light), it cannot be used in this case as there has no suitable chromophores existed for the epoxides. However, the predicted ECD can still be generated through the calculation (listed below), but it will not give any useful information in assigning the stereochemistry. This is the limitation for this particular calculation as it cannot register there has no suitable chromophores in the epoxides.

Table:16 ECD spectrums of the Epoxide 3

Epoxide 3 RR DOI:10042/27324	Epoxide 3 SS DOI:10042/27327

Table:17 ECD spectrums of the Epoxide 4

Epoxide 4 1R,2S DOI:10042/27323	Epoxide 4 1S,2R DOI:10042/27322
Epoxide 4 1R,2R DOI:10042/27342	Epoxide 4 1S,2S DOI:10042/27342

Vibrational Circular Dichroism (VCD)

Unlike ECD, VCD can be used in assigning the absolute chemistry of the epoxides, see that in table below. For a same pair of enantiomer, the VCD spectrums are mirror images to each other. This is because of the two complete and opposite vibrational environments presented in the enantiomers pair. Unfortunately, the instrument is not available in the department, hence it cannot be done.

Table:18 VCD spectrums of the Epoxide 3

Epoxide 3 RR DOI:10042/27355	Epoxide 3 SS DOI:10042/27334

Table:19 VCD spectrums of the Epoxide 4

Epoxide 4 1R,2S DOI:10042/27332	Epoxide 4 1S,2R DOI:10042/27331
Epoxide 4 1R,2R DOI:10042/27330	Epoxide 4 1S,2S DOI:10042/27333

Using the ( Calculated )properties of the Transition state of the reaction

The energies of the transition state of the shi epoxidation for both trans-stilbene and 1,2-dihydronaphthalene (the data were supplied by Prof. Herny Rzepa) were compared and this allows us to determine the relative proportion of the enantiomer that will be produced in the reaction. By converting the free energy difference between the two enantiomers to K with the equation of deltaG=-RTln K. The ratio of concentrations of the two enantiomers can be determined, as well as the enantiomers excess of the specific epoxide.

Based on the calculated thermodynamic properties in the table below, it can be seem that the transition state of epoxide 3 RR and epoxide 4 SR are thermodynamically more stable within their enantiomer pair. For the shi epoxidation, the RR configuration is predicted to be highly favoured in the formation of the epoxide 3 (with predicted 99.2 % ee), whereas the SR configuration is predicted to be relatively favoured in the formation of the epoxide 4 (with predicted 30 % ee, which is much smaller than epoxide 3). The predications on which enantiomer of epoxide is favoured and the enantiomer excess are matched with the literature value too; see the table in the ORP section.

Table:20 Comparisons of the free energies of the transition states between enantiomers

	Epoxide 3	Epoxide 3		Epoxide 4	Epoxide 4
	RR	SS		RS	SR
Free Energies of Transition state 1	-1534.687808	-1534.683440		-1381.120782	-1381.131343
Free Energies of Transition state 2	-1534.687252	-1534.685089		-1381.125886	-1381.116109
Free Energies of Transition state 3	-1534.700037	-1534.693818		-1381.134059	-1381.126039
Free Energies of Transition state 4	-1534.699901	-1534.691858		-1381.126722	-1381.136239
Average Free Energies of Transition state	-1534.693750	-1534.688541		-1381.126862	-1381.127433
Difference in free energies	(RR-SS) -0.00520875			(RS-SR)0.0005705
Ratio of concentration (K)	248			0.547
Relative Population (%)	99.6	0.4		35	65
Enantiomeric excess	99.2% ee for RR			30% ee for SR

Investigating the non-covalent interactions in the active-site of the reaction transition state

For 1,2-dihydronapthalene with Shi catalyst

Non-covalent interactions (NCI) consisting of hydrogen boning, electrostatic and dispersion interaction, it can be shown as electron density. Under the NCI analysis of the transition state 4 of 1,2-dihydronaphthalene in shi epoxidation, there has green (mildly attractive attraction) and even blue (very attractive attraction) region between the active shi catalyst and the C-C bond that epoxide will be formed at. This indicated that the substrate and active catalyst were orientated themselves in a way to maximise the interaction, which enable the epoxidation to happen. The direction of the shi active catalyst approached and interacted with the 1,2-dihydronaphthalene ( see in the diagram below) may be the origin of the stereochemistry of the epoxide 4 (RS or SR) .

Table:21 NCI of Epoxide 4 RS and SR

Epoxide 4 RS	Epoxide 3 SR

Investigating the Electronic topology (QTAIM) in the active-site of the reaction transition state

For the orientation of the active shi catalyst to the1,2-dihydronaphthalene that was shown in the NCI section, it can be confirmed again by the QTAIM analysis. The red arrows indicate weak non-covalent BCP involved the reaction site of the epoxidation whereas other remained weak non-covalent BCP involved maintaining the orientation of the pre-catalyst to the substrate.

Table:22 QTAIM of Epoxide 4 RS and SR

Epoxide 4 RS	Epoxide 4 SR

New Candidates for investigations

By searching on Reaxys with the required range of molecular weight and ORP, two possible new candidates of epoxide and their corresponding alkene were found. The epoxides are (1R,4R)-pulegone oxide and (1R,4S)-pulegone oxide with their structure are listed in diagram below. They both can be synthesised from the (+) Pulegone (with potassium hydroxide and dioxygen peroxide), which is available in the catalogue of the Sigma Aldwich and costs around £63.60 for 100G. Therefore, they are the suitable epoxides for the future investigation.

Table:23 Possible Epoxide candidates

	(1R,4R)-pulegone oxide	(1R,4S)-pulegone oxide
Condition	C=0.03 , ethanol, 324 nm, 25 degree celsius	C=0.03 , ethanol, 327 nm, 25 degree celsius
Rotation [Aplha]	853.9 deg	-1177.9 deg

Limitations of the software and further works

Limitations of the software

• Avagordro: For small molecule, it is easy to draw the structure within the program directly, but it is not easy for big molecule. The big molecule can be drawn instead with ChemDraw first and import into the program. However, the stereochemistry of the molecules was lost in the import and there also had a minor change to the configuration of the structure.
• QTAIM: The coordinates of the molecules cannot be saved; therefore screenshots are needed. It will be good if the result diagram can be rotated in 3D after uploaded to the wiki page, as it is easier for understanding the analysis.
• Gassview: It takes a sufficient time for running and it needs specific files (e.g fchk, log etc) in order to get the required information on the molecule. However, it is able to generate the predicted UV, IR, NMR, ECD and VCD spectrums for the specific molecule.

Further work

• Investigate the suggested candidates of the epoxide with the similar approach above
• Repeat the optimisation of the molecules with ChemBIO3D and compare the results to the one obtained in this investigation. This is because all the molecule were optimised with Avogadro in this case.
• Although the calculation of the coupling constant of the epoxide were obtained in this investigation, time was not sufficient to combine them with the chemical shift value and stimulate the actual spectrum from gNMR. It will be good if more guideline on how to use gNMR is provided in the Toolbox section,so the actual NMR can be stimulated.
• Search for the ORP for epoxide 4 RR and SS in other chemical database and compare them with the calculated value above.