Rep:Mod:wc1911

Part 1

The Hydrogenation of Cyclopentadiene Dimer

Introduction

At room temperature, Cyclopentadiene dimerises to produce dicyclopentadiene via Diels-Alder reaction. Specifically, the endo dimer 2 is preferred than the exo dimer 1. To explore the reason accounts for this phenomenon, both 1 and 2 were drew and optimized using MMFF94s force field in Avogadro. Also, hydrogenation of endo dimer can be done across two different bonds, which results in two different products 3 and 4.

reactions schemes

exo and endo dimer

Table 1: optimized structures and energy calculation of 1/2

molecules	1(dimer exo)	2(dimer endo)
structure	1	2
Total bond stretching energy(kcal/mol)	3.54303	3.46790
Total angle bending energy(kcal/mol)	30.77273	33.18940
Total stretch bending energy(kcal/mol)	-2.04142	-2.08218
Total tortional energy(kcal/mol)	-2.73046	-2.94949
Total out-of-plane bending energy(kcal/mol)	0.01477	0.02183
Total Van Der Waals energy(kcal/mol)	12.80111	12.35869
Total electronic energy(kcal/mol)	13.01366	14.18452
Total energy(kcal/mol)	55.37342	58.19067

analysis

endo dimer forming process

As can be seen from the table above, endo dimer has a higher energy geometry than exo dimer, which means exo dimer is thermodynamically preferred product. But in fact, endo dimer is the preferred product, which means this dimerisation process should be under kinetic control via a more stable endo transition state. Orbitals overlap during endo transition state is shown on the right. To explain the difference of energies of exo and endo dimer, bond angles are labelled in the picture, since angle bending energy is the main resource of this difference. Compared to supposed angles(sp3 109.5 and sp2 120), endo dimer deviates more than exo does, which leads to higher total energy.

Hydrogenation products

Table 2: optimized structures and energy calculation of 3/4

molecules	3	4
structure	3	4
Total bond stretching energy(kcal/mol)	3.31178	2.82313
Total angle bending energy(kcal/mol)	31.93329	24.68580
Total stretch bending energy(kcal/mol)	-2.10224	-1.65722
Total tortional energy(kcal/mol)	-1.46857	-0.37855
Total out-of-plane bending energy(kcal/mol)	0.01309	0.00028
Total Van Der Waals energy(kcal/mol)	13.63885	10.63704
Total electronic energy(kcal/mol)	5.11949	5.14701
Total energy(kcal/mol)	50.44569	41.25749

analysis

Same computational procedures are performed on 3 and 4 as 1 and 2. Molecule 3 has higher total energy than molecule 4 apparently, which can be explained by the large difference of their angle bonding energies. Obviously, from the labelled angles shown, molecule 3 angles deviates more. So if hydrogenation is under kinetic control, product 3 may dominates, while thermodynamic control will favor product 4 definitely. Reactant 2 transformation into products 3 and 4 should be thermodynamically favored as products are lower energy geometries.

Atropisomerism in an Intermediate related to the Synthesis of Taxol

9 and 10

Intermediate 9 or 10 in the total synthesis of Taxol contains a carbonyl group pointing up or down, which can be converted to each other through bond rotation and so defined as Atropisomers. Using Avogadro MMFF94(s) force field to optimize both and to calculate energies. Compared to molecule 9, molecule 10 has lower angle bending energy due to less deviation from theoretical bond angle.(Table 4) Also, this low energy of molecule 10 contributes to the stability of it, which proved intolerance of high temperature under which slow decomposition of molecule 10 was observed.

To explain the slow reactivity of intermediates 9 and 10, olefin strain energy is introduced, defined as the difference between the strain energy of an olefin and its corresponding saturated hydrocarbon(except carbonyl group). As can be seen from the table below, both 9 and 10 have lower energy than their parent molecules and this stability accounts for their relative inertness.

Table 3: Optimized structure and energy calculation of 9/10 and their parent hydrocarbon

molecules	9	10	parent 9	parent 10
	9	10	10	10
Total bond stretching energy(kcal/mol)	7.65562	7.73198	6.95860	6.86407
Total angle bending energy(kcal/mol)	28.27693	19.60760	32.05834	25.84737
Total stretch bending energy(kcal/mol)	-0.08393	-0.06128	0.30550	0.51634
Total tortional energy(kcal/mol)	0.33595	3.23569	9.46216	10.93646
Total out-of-plane bending energy(kcal/mol)	0.97742	0.86280	0.25479	0.09975
Total Van Der Waals energy(kcal/mol)	33.08578	34.99921	32.72025	33.16216
Total electronic energy(kcal/mol)	0.30592	-0.04593	--	--
Total energy(kcal/mol)	70.55371	66.33007	81.75963	77.42615

Table 4.bond angles

carbons	angles supposed	9	10
6,9,14	109.5	105	111
14,9,13	109.5	103	109
36,13,21	120	117	120
13.21.25	109.5	118	108
25.21.24	109.5	103	109

Spectroscopic Simulation using Quantum Mechanics

Using Avogadro to sketch and to optimize structures 17 and 18(MMFF94s), after which calculation of the geometry(17 chair) at the density functional level(DFT) is carried out by sending it to HPC system. The following work done is to compare this computational NMR spectrum with literature experimental one.

After optimization is carried out on molecule 17, it can be observed that the hexane ring of it has a chair form while a twisted boat form has been obtained on molecule 18. Adjusting the atoms positions of molecule 18 to get a lower energy chair form.

So I use the naturally occurred molecule 17 chair form to have NMR comparison and 18 chair form to compare the relative energies of these two isomeric configurations.

Table 1: structures analysis of 17/18

molecules	17 chair form	18 chair form
structure	1	2
Energy	439.461 kJ/mol	420.574 kJ/mol

Analysis

17 can be completely transformed into its conformational isomer 18 which possesses lower energy. Several bonds rotation must be done in this process and the most obvious change is the turn down of the pointing up carbonyl group in 17. This lower energy isomer 18, however, brings the methyl substituent(next to the carbonyl group) closer to the syn-oriented bridgehead methyl group, as shown on table above.

Procedure using the HPC and analysis

Table 2: NMR(H)of molecule 17( ref.chloroform)

shift(ppm)	Degeneracy	Atoms	Reference values	comparison
5.1507207448	1.0000	17	'H NMR (300 MHz, CDCl3) δ4.84(1 H) ,3.40-3.10(m,4 H), 2.99(dd,1 H) ,2.80-1.35(series of m,14 H), 1.38(s,3 H), 1.25(s,3H),1.10(s,3 H),1.00-0.8(m,1 H)
3.3080497824	1.0000	50
3.2207388624	1.0000	51
3.1592422462	1.0000	23
3.0146197695	2.0000	53,52
2.7156706265	2.0000	4,20
2.6367920939	1.0000	42
2.3970307659	4.0000	14,15,35,19
2.2736741818	2.0000	5,7
2.1222660004	2.0000	28,12
1.9542223978	1.0000	34
1.9034967023	1.0000	30
1.7457288626	1.0000	47
1.5957364246	3.0000	8,31,38
1.4893838736	1.0000	27
1.1633867526	1.0000	45
0.9073763124	3.0000	40,43,39
0.8236499126	1.0000	44
0.5920733176	1.0000	46

Table 3: NMR(C) molecule 17(chair)

shift(ppm)	Degeneracy	Atoms	Reference	comparison
216.1000554247	1.0000	13	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
145.1230518451	1.0000	3
124.6989245528	1.0000	10
90.6460853480	1.0000	22
60.6391957007	1.0000	18
57.0551827243	1.0000	21
52.4718298107	1.0000	6
51.5473831103	1.0000	11
46.6913275278	1.0000	9
45.9547148608	1.0000	48
42.1758310396	1.0000	29
40.5782361033	1.0000	49
35.3211660520	1.0000	16
31.0114109626	1.0000	1
29.3385433737	2.0000	24,25
27.0963621866	1.0000	2
26.4009919833	1.0000	37
22.9019947936	1.0000	26
19.7261195422	1.0000	41

NMR diagram(chloroform)

molecule 17(H)chair	molecule 17(C) chair

analysis

It can be seen from above scatter lines that ¹H chemical shifts of experimental spectrum differs from the computational one, which may due to different conditions included in these spectra records(e.g. solvent, temperature, pressure.etc). The reason for the almost overlap lines of ¹³ C NMR is the scale of the diagram limits the reveal of deviations. However, deviations in both cases(1H and 13C) actually are small, which means the experimental data matches the computational one well.

Table 4:Energies values

Type of energy(Hartree)	Molecule 17(chair)	Molecule 18(chair)
Zero-point correction	0.468013	0.467883
Thermal correction to Energy	0.489499	0.489293
Thermal correction to Enthalpy	0.490443	0.490237
Thermal correction to Gibbs Free Energy	0.421225	0.421126
Sum of electronic and zero-point Energies	-1651.414395	-1651.417439
Sum of electronic and thermal Energies	-1651.392910	-1651.396030
Sum of electronic and thermal Enthalpies	-1651.391965	-1651.395086
Sum of electronic and thermal Free Energies	-1651.461183	-1651.464197

analysis

It can be concluded from both Table 4 Energy values and Table 1 Energy values that, molecule 18(in which six carbons ring takes chair form) is lower in terms of energy. But to transform 17 to 18,re-flux is needed to make this transformation done completely , which may due to high activation energy needed to rotate bonds. However, as 18 is lower in energy, complete transformation can be observed.

Part 2

Shi Fructose catalyst

Species 21 is a stable precursor to the Shi Fructose catalyst. '

Table 5:bond length

Bond assignment	atoms	bond length
a	1O-2C	1.420 А
b	3O-2C	1.405 А
c	3O-4C	1.460 А
d	5O-4C	1.406 А
e	6O-7C	1.442 А
f	8O-7C	1.430 А

2

analysis

Typical bond length of C-O bond is 1.43 А. As can be seen from the Table 5, both bond a and b are shorter than the typical bond length, which can be explained by orbital overlaps between these bonds and the carbonyl π* bond. The torsional angle betwwen bond a and carbonyl group is 114 and the angle between b and carbonyl group is 123, both allow overlap well. Both the lone pairs shown on the picture can be donated to bond a or bond b, which is allowed by the axial position. So the reason accounts for the longer bond length of a than b is ³O connected to tertiary ⁴C donates lp more, which shortens bond b but lengthens bond a.

As ³O donates much electron density into interactions mentioned above,its ability of donating the other lp on it to bond d is weaker than donation of ⁵O to bond c, which makes bond c longer than d apparently.

The structure of 21 doesn't allow the orbital overlap between ⁶O-C and the carbonyl group because the Torsional Angle is 20.84 which is not good. But due to the inductive effect drawn, lp on ⁶O donates less than lp on ⁸O does, which leads to longer bond e than f.

The Jacobsen epoxidation catalyst

2

structure analysis

In typical organic compounds, maximum attraction occurs at the distances 2.4 А for typical pairs of non-bonded H---H atoms and repulsion dominates when the distance < 2.1 А. Three of the distances measured above is attractive while the other one is repulsive interaction and this contributes to overall stabilization of the molecule. An interesting thing can be noted is that the Mn center adopts square pyramid structure other than trigonal bi-pyramid structure. Because four donor groups (except Cl)are on the same plane in sq.py structure, which avoids large torsional strain as in trigonal bi-pyramid, this structure is the preferred low energy structure.

Epoxidation

Table 6: structures analysis of epoxides

molecules	β-methyl strene oxide(RR)	β-methyl strene oxide(SS)	trans-Stilbene oxide(RR)	trans-Stilbene oxide(SS)
structure	1	2	2	2
Energy(kJ/mol)	96.8030	96.8002	165.198	165.211

Table 7:NMR data(TMS B3LYP/6-31G(d,p) Chloroform)

1H β-methyl styrene oxide	13C β-methyl styrene oxide	1H Stilbene oxide	13C Stilbene oxide

Assigning the absolute configuration of the product(ORP)

Table 8:Optical rotations

	Literature(2RR)	ORP(2RR)	Literature(2SS)	ORP(2SS)
condition	0.32g/100ml (concentration) ,90%ee, CHCl3(solvent), 250C, 589nm	CAM-B3LYP/6-311++g(2df,p),polar(optrot),scrf(cpcm,solvent=chloroform)	1g/100ml (concentration) ,99%ee, CHCl3(solvent), 250C, 589nm	CAM-B3LYP/6-311++g(2df,p),polar(optrot),scrf(cpcm,solvent=chloroform)
Rotation	44.3 deg	46.79 deg	-41.8 deg	-47.77 deg

Table 9:Optical rotations

	Literature(3RR)	ORP(3RR)	Literature(3SS)	ORP(3SS)
condition	0.73g/100ml (concentration) ,97%ee, CHCl3(solvent), 250C, 589nm	CAM-B3LYP/6-311++g(2df,p),polar(optrot),scrf(cpcm,solvent=chloroform)	0.56g/100ml (concentration) ,89%ee, CHCl3(solvent), 200C, 589nm	CAM-B3LYP/6-311++g(2df,p),polar(optrot),scrf(cpcm,solvent=chloroform)
Rotation	334.6 deg	297.7 deg	-205.2 deg	-298.24 deg

analysis

It can be noted from the table above that enantiomers of same molecule give out similar value of the optical rotations but opposite sign. Also, the computational value calculated are close to the literature result, although deviations exist. It can be concluded that the computational method used is reasonable and the literature records are correct.

Assigning the absolute configuration of the product(VCD)

Table 9:VCD (B3LYP/6-31G(d,p))

2RR	2SS
3RR	3SS

analysis

It can be observed obviously that enantiomers have complete reverse VCD spectra(reflect along x-axis), which means the vibrational circular dichroism(VCD) should be useful in assigning absolute configuration. However, the appropriate instrument is not available in the department. It should be mentioned another technique can be used in identifying absolute configuration, the electronic circular dichroism(ECD), which is the UV/Vis spectrum recorded with polarised light. Although ECD is extremely useful in assigning absolute configurations always, absence of chromophore in the epoxides makes ECD useless here.

Using the Transition States Properties for the reaction

Introduction

As expoxidation products of same molecule can be enantiomeric and energies are different between these products, selectivity should exist and the enantiomeric excess can be computational calculated by considering energies of TS. Then this computational result can be used to check the enantiomeric assignment obtained before which is done by comparing computed and calculated optical rotations. Equation used in calculation is ΔG(TS)=-RTlnK and K is the equilibrium constant.

Energies obtained from given data and calculation

Table 10:Sum of electronic and thermal energies(Hartree)

data given	2RR	2SS	3RR	3SS
1	-1343.022970	-1343.017942	-1534.687808	-1534.683440
2	-1343.019233	-1343.015603	-1534.687252	-1534.685089
3	-1343.029272	-1343.023766	-1534.700037	-1534.693818
4	-1343.032433	-1343.024742	-1534.699901	-1534.691858
average	-1343.02598	-1343.020513	-1534.69375	-1534.688551
Energy difference	0.005467		0.005199
equi constant K	328.13		247
Enantiomer excess	99.7%		99.6%

analysis

It can be concluded that in both cases,molecule 2(β-methyl styrene oxide) or 3(tans-Stilbene oxide), RR species are lower energy than SS species, which indicates that amount of RR overrides SS and that enantiomeric excess are calculated above. However, the enantiomeric values calculated are too high which are not same as experimental measured values(Table 8); it can be explained by the real conditions involved in experiments, which were not considered in computational calculation, such as temperature,solvents used and pressure, etc.

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

Table 9:NCI

2RR	2SS

Analysis

Pictures shown above reveal the non-covalent interactions, which include electrostatic attractions, hydrogen bonds and dispersion-like close approaches of pair of atoms. There are colorful rings in both RR and SS, which represent bond forming interaction there, while green areas mean mildly attraction. It may be seen from the pictures that the arrangement and orientation of atoms in RR transition state give out a larger green area than SS TS, which means RR TS should be more stable due to stronger attraction. It is where stereo-selectivity originating.

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

Blue arrow shown above indicates a BCP(bond critical point) which is associated with a covalent bond(forming new C--O). At the same time, two red arrows indicate two BCP which is associated with a non-covalent bond, which form between O(on 5 member ring the catalyst) and H connected to the reacting carbon center. This non-covalent bonds definitely orient where H points to and orient where epoxidation carries out, which makes sure RR selectivity to some extend.

Suggesting new candidates for investigations

corresponding alkene

Optical Rotatory power

conditions	c=0.03, solvent(ethanol),324 nm, 250C	c=0.03, solvent(ethanol),327 nm, 250C
OR	853.9 deg	-1177.9 deg

The starting material for the products shown above is Pulegone and the products are synthetically accessible, which can be done by mCPBA.