Appendices¶

Working iPython notebook files for the processing of data relating to benchmarks and all raw data for the OEEF scanning sections can be found at GitHub. Due to the enormity of the undertaking, geometries have not been included and due to the enormity of their file sizes, PyMOL files have not been shared either, however both are available upon request.\(\newcommand{\va}{V\cdot\AA^{-1}}\newcommand{\eh}{E_h}\newcommand{\dc}{^\circ C}\newcommand{\kcalmol}{Kcal\cdot mol^{-1}}\newcommand{\kjmol}{KJ\cdot mol^{-1}}\)

A Raw data from the pathway benchmarking in Section 3.1 ¶

Table A.1: Raw \(\Delta G^{\circ}\) from the benchmarking of the reaction pathways in Section 3.1. The blank cells pertain to calculations that were not performed.

Pathway	Energy (\(E_h\))
	Reactant	Transition State 1	Intermediate	Transition State 2	Product
Non-activated	-709.212961	-709.171714			-709.187604
Brønsted Acid 1		Barrierless	-709.620615	-709.599167	-709.634264
Brønsted Acid 2		-786.010860	-709.596855	Barrierless	-709.648273
Brønsted Base		-785.166022	-708.726998	-708.701422	-708.755359
Lewis Acid		Barrierless	-1033.879641	-1033.855176	-1033.885971
Lewis Base		Barrierless	-960.453357	-960.453357	-960.483276

Table A.2: raw \(\Delta G^{\circ}\) of the species used top balance the reaction trajectories in Section 3.1

Additive	Energy (\(E_h\))
\(\ce{H2O}\)	-76.440078
\(\ce{H3O+}\)	-76.830283
Piperidine	-251.221244
\(\ce{BF3}\)	-324.652124

Table A.3: Transition state imaginary frequencies and calculated transmission coefficients for the intermediate formation and cyclisation steps respectively, for the reaction pathways benchmarked in Section 3.1

	Frequency 1 (\(cm^{-1}\))	\(\kappa_1\)	Frequency 2 (\(cm^{-1}\))	\(\kappa_2\)
Brønsted Acid 1	Barrierless		-382.40	1.157
Brønsted Acid 2	-1228.66	13.612	Barrierless
Brønsted Base	-1200.35	1.185	-534.59	1.342
Lewis Acid	Barrierless		-427.78	1.202
Lewis Base	Barrierless		-548.23	1.365


PES scan of the Lewis acid (\(\ce{BF3}\)) attaching into 1, scanning along the \(\ce{O-B}\) bond length.	PES scan of the Lewis base (\(\ce{piperidine-}\)) deprotonating the 1 amine, scanning along the amine \(\ce{N-H}\) bond length.

PES scan of the protonation of the ‘Brønsted acid 1’ pathway (1 \(\to\) 7) scanning along the forming \(\ce{O-H}\) bond length.	PES scan of the cyclisation of the ‘Brønsted acid 2’ pathway (11 \(\to\) 4) scanning along the forming \(\ce{N-C}\) bond length.

Figure A.1: PES scans along the reaction coordinate for all barrierless steps in the various pathways.

B Raw data and reaction trajectories from Section 3.4 ¶

Table B.1: Raw \(\Delta G^\circ\), transition state imaginary frequencies, and tramsission coefficients for the benchmarks performed in Section 3.4

\(\vec F\) (\(\va\))	\(\Delta G\) Reactant (\(\eh\))	\(\Delta G\) Transition State (\(\eh\))	\(\Delta G\) Product (\(\eh\))	\(\bar\nu\)	\(\kappa\)
Gas
None	-708.898472	-708.838431	-708.840519	-472.60	1.243
0.1 (Catalytic)	-708.898222	-708.841845	-708.845638	-434.69	1.210
0.1 (S anti-selective)	-708.898075	-708.836571	-708.838916	-472.30	1.247
0.1 (S anti-selective)	-708.898395	-708.839004	-708.840006	-472.70	1.166

Hexane
None	-708.906434	-708.853442	-708.8 58711	-489.29	1.276
0.1 (Catalytic)	-708.906599	-708.857667	-708.865868	-465.54	1.246
0.1 (S anti-selective)	-708.906126	-708.851179	-708.857311	-487.68	1.274
0.1 (S anti-selective)	-708.906126	-708.851179	-708.857311	-487.68	1.257

DCM
None	-708.916525	-708.871672	-708.885508	-486.00	1.266
0.1 (Catalytic)	-708.915264	-708.875421	-708.890046	-460.69	1.240
0.1 (S anti-selective)	-708.914632	-708.867875	-708.879710	-484.81	1.271
0.1 (S anti-selective)	-708.915696	-708.872193	-708.883006	-462.14	1.242

Ethanol
None	-708.916180	-708.872721	-708.885927	-482.10	1.267
0.1 (Catalytic)	-708.916826	-708.878676	-708.894984	-457.65	1.236
0.1 (S anti-selective)	-708.916163	-708.870769	-708.884170	-486.67	1.273
0.1 (S anti-selective)	-708.917107	-708.875217	-708.887664	-458.69	1.238

DMSO
None	-708.916626	-708.873640	-708.887326	-480.16	1.264
0.1 (Catalytic)	-708.917322	-708.879704	-708.896476	-456.87	1.235
0.1 (S anti-selective)	-708.916525	-708.871672	-708.885508	-486.00	1.272
0.1 (S anti-selective)	-708.916525	-708.871672	-708.885508	-486.00	1.235

Water
None	-708.916820	-708.874020	-708.887956	-481.96	1.267
0.1 (Catalytic)	-708.917509	-708.880107	-708.897132	-456.64	1.235
0.1 (S anti-selective)	-708.916764	-708.872039	-708.886105	-486.57	1.273
0.1 (S anti-selective)	-708.917400	-708.876558	-708.889680	-459.05	1.238

Figure B.1: Reaction trajectories for the relaxed benchmarks performed in Section 3.4

C Electron density difference maps of the derivatives discussed in Section 3.5 ¶



\(\ce{R1 = H, R2 = H}\) \(F=\) S selective	\(\ce{R1 = H, R2 = H}\) \(F=\) S anti-selective	\(\ce{R1 = H, R2 = NH2}\) \(F=\) S selective	\(\ce{R1 = H, R2 = NH2}\) \(F=\) S anti-selective

\(\ce{R1 = H, R2 = NO2}\) \(F=\) S selective	\(\ce{R1 = H, R2 = NO2}\) \(F=\) S anti-selective	\(\ce{R1 = NH2, R2 = H}\) \(F=\) S selective	\(\ce{R1 = NH2, R2 = H}\) \(F=\) S anti-selective

\(\ce{R1 = NH2, R2 = NH2}\) \(F=\) S selective	\(\ce{R1 = NH2, R2 = NH2}\) \(F=\) S anti-selective	\(\ce{R1 = NH2, R2 = NO2}\) \(F=\) S selective	\(\ce{R1 = NH2, R2 = NO2}\) \(F=\) S anti-selective

\(\ce{R1 = NO2, R2 = H}\) \(F=\) S selective	\(\ce{R1 = NO2, R2 = H}\) \(F=\) S anti-selective	\(\ce{R1 = NO2, R2 = NH2}\) \(F=\) S selective	\(\ce{R1 = NO2, R2 = NH2}\) \(F=\) S anti-selective

	\(\ce{R1 = NO2, R2 = NO2}\) \(F=\) S selective	\(\ce{R1 = NO2, R2 = NO2}\) \(F=\) S anti-selective

Figure C.1: Electron density difference isosurfaces following an isovalue of 0.0002 for the optimal \(0.1\:\va\) S selective/S anti-selective OEEF directions for each of the derivatives, calculated at M06-2X/6-31+G*, solvated in CPCM ethanol. The red and blue isosurfaces represent regions of increased and decreased electron density respectively. The yellow arrow is a representation of the direction of the applied field vector.

D Raw data and reaction trajectories from Section 3.6¶

Figure D.1: Raw \(\Delta G^\circ\), transition state imaginary frequencies, and tramsission coefficients for the benchmarks performed in Section 3.6

\(\vec F\) (\(\va\))	\(\Delta G\) Reactant (\(\eh\))	\(\Delta G\) Transition State (\(\eh\))	\(\Delta G\) Product (\(\eh\))	\(\bar\nu\)	\(\kappa\)
Non-derivatised (\(\ce{R1,R2=H}\))
None	-708.916180	-708.872721	-708.885927	-482.10	1.267
0.1 (Catalytic)	-708.916826	-708.878676	-708.894984	-457.65	1.236
0.1 (S anti-selective)	-708.916163	-708.870769	-708.884170	-486.67	1.273
0.1 (S anti-selective)	-708.917107	-708.875217	-708.887664	-458.69	1.238
0.2 (Catalytic)	-708.913028	-708.876643	-708.903230	-431.65	1.207
0.2 (S anti-selective)	-708.916849	-708.868621	-708.882899	-488.55	1.276
0.2 (S anti-selective)	-708.918317	-708.877299	-708.890741	-436.64	1.212

Derivatised (\(\ce{R1,R2=NO2}\))
None	-1117.798403	-1117.747859	-1117.759120	-511.75	1.308
0.1 (Catalytic)	-1117.792269	-1117.752700	-1117.768354	-489.44	1.277
0.1 (S anti-selective)	-1117.797376	-1117.744906	-1117.758071	-517.59	1.316
0.1 (S anti-selective)	-1117.801593	-1117.745641	-1117.760201	-486.77	1.273
0.2 (Catalytic)	-1117.787395	-1117.750533	-1117.775299	-443.38	1.220
0.2 (S anti-selective)	-1117.795114	-1117.741251	-1117.757556	-527.43	1.331
0.2 (S anti-selective)	-1117.803489	-1117.748212	-1117.761122	-484.36	1.27

Derivatised (\(\ce{R1,R2=NH2}\))
None	-819.567938	-819.527946	-819.541147	-453.96	1.232
0.1 (Catalytic)	-819.572619	-819.535792	-819.550188	-427.28	1.202
0.1 (S anti-selective)	-819.569241	-819.526057	-819.540957	-463.67	1.244
0.1 (S anti-selective)	-819.569181	-819.530218	-819.544841	-432.05	1.207
0.2 (Catalytic)	-819.576743	-819.539267	-819.556151	-418.99	1.193
0.2 (S anti-selective)	-819.570568	-819.525077	-819.541019	-468.29	1.249
0.2 (S anti-selective)	-819.572210	-819.531785	-819.548810	-407.72	1.182

E Transition state geometries and reaction trajectories from the OEEF perturbed benchmarks in Section 3.6 ¶

Figure E.1: Reaction trajectories for the benchmarks performed in Section 3.6


\(\ce{R1,R2 = H}\) \(\vec F=0.1\:\va\) R selective	\(\ce{R1,R2 = H}\) \(\vec F=0.1\:\va\) S selective	\(\ce{R1,R2 = H}\) \(\vec F=0.1\:\va\) Catalytic

\(\ce{R1,R2 = H}\) \(\vec F=0.2\:\va\) R selective	\(\ce{R1,R2 = H}\) \(\vec F=0.2\:\va\) S selective	\(\ce{R1,R2 = H}\) \(\vec F=0.2\:\va\) Catalytic

\(\ce{R1,R2 = NO2}\) \(\vec F=0.1\:\va\) R selective	\(\ce{R1,R2 = NO2}\) \(\vec F=0.1\:\va\) S selective	\(\ce{R1,R2 = NO2}\) \(\vec F=0.1\:\va\) Catalytic

\(\ce{R1,R2 = NO2}\) \(\vec F=0.2\:\va\) R selective	\(\ce{R1,R2 = NO2}\) \(\vec F=0.2\:\va\) S selective	\(\ce{R1,R2 = NO2}\) \(\vec F=0.2\:\va\) Catalytic

\(\ce{R1,R2 = NH2}\) \(\vec F=0.1\:\va\) R selective	\(\ce{R1,R2 = NH2}\) \(\vec F=0.1\:\va\) S selective	\(\ce{R1,R2 = NH2}\) \(\vec F=0.1\:\va\) Catalytic

\(\ce{R1,R2 = NH2}\) \(\vec F=0.2\:\va\) R selective	\(\ce{R1,R2 = NH2}\) \(\vec F=0.2\:\va\) S selective	\(\ce{R1,R2 = NH2}\) \(\vec F=0.2\:\va\) Catalytic

Figure E.2: Transition state geometries and reaction trajectories from the OEEF perturbed benchmarks in Section 3.6

F Full theoretical choices, approximations and precision used throughout the project ¶

Software Package	Job type	Functional	Basis set	Solvation	Convergence criteria	Integration grid	Approximations	Field
Pathway Benchmarking: low level opt
ORCA 5.0.1¹	Opt	M062X⁶	aug-cc-pVTZ²³ aug-cc-pVTZ/JK	CPCM¹⁸⁴ Ethanol	Tightscf tightopt	Defgrid3	RIJK¹⁹	No
Pathway Benchmarking: High level opt
ORCA 5.0.1¹	Opt	ωB97M-V⁹	Def2-QZVPP¹⁰def2/j¹¹	SMD⁵ Ethanol	Verytightscf tightopt	Defgrid3	RIJCosX¹²	No
Pathway Benchmarking: TS Searching NEB
ORCA 5.0.1¹	NEB-TS	M062X⁶	aug-cc-pVTZ²³ aug-cc-pVTZ/JK	CPCM¹⁸⁴ Ethanol	Tightscf tightopt	Defgrid3	RIJK¹⁹	No
Pathway Benchmarking: High level opt - TS
ORCA 5.0.1¹	OptTS	ωB97M-V⁹	Def2-QZVPP¹⁰def2/j¹¹	SMD⁵ Ethanol	Verytightscf tightopt	Defgrid3	RIJCosX¹²	No
Pathway Benchmarking: PES scanning
ORCA 5.0.1¹	SCAN	ωB97M-V⁹	Def2-TZVPD¹⁰Def2/J¹¹	SMD⁵ Ethanol	Tightscf	Defgrid2	RIJCosX	No
Pathway Benchmarking: High level opt Frequencies
ORCA 5.0.1¹	Freq	ωB97M-V⁹	Def2-QZVPP¹⁰Def2/j¹¹	SMD⁵ Ethanol	Verytightscf	Defgrid3	RIJCosX¹²	No
Partial charge determination
Multiwfn 3.8¹³	CHELPG²⁰ charges based on the wavefunctions calculated above, using a grid density of \(0.1\:\AA\).
	Multiwfn uses the LIBRETA²¹ package for evaluation of the electrostatic potential
Benchmarking barrier as a function of \(F_y\)
ORCA 5.0.1¹	Single Point	M062X⁶	6-31+G(d)⁷⁸	SMD⁵ Ethanol/none	Standard	Defgrid3	none	Yes
Benchmarking R/S separation as a function of \(F_z\)
ORCA 5.0.1¹	Single Point	M062X⁶	6-31+G(d)⁷⁸	SMD⁵ Ethanol/none	Standard	Defgrid3	none	Yes
Benchmarking catalysis/separation (\(F_y\)/\(F_z\)) as function of dielectric medium
ORCA 5.0.1¹	Single Point	M062X⁶	6-31+G(d)⁷⁸	CPCM¹⁸⁴ varied	Standard	Defgrid3	none	Yes
OEEF scans
Psi4 1.4¹⁵¹⁶¹⁷	Opt	M062X⁶	6-31+G(d)⁷⁸	none	Standard	590/99	none	Yes
EDD isosurfaces
Psi4 1.4¹⁵¹⁶¹⁷	SP	M062X⁶	6-31+G(d)⁷⁸	none/CPCM¹⁸⁴	Standard	590/99	none	Yes
Relaxed OEEF Solvent Benchmarking
ORCA 5.0.1¹	Opt NumFreq	M062X⁶	6-31+G(d)⁷⁸	CPCM¹⁸⁴ varied	Tightopt	Defgrid3	none	Yes/No
Derivative Efield scans
Psi4 1.4¹⁵¹⁶¹⁷	Opt	M062X⁶	6-31+G(d)⁷⁸	CPCM¹⁸⁴	Standard	590/99	none	Yes
Point charge perturbation
ORCA 5.0.1¹	Single Point	M062X⁶	6-31+G(d)⁷⁸	none	verytightscf	Defgrid3	none	Yes

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