Another long C-C bond

Uncategorized Steven Bachrach 10 Jul 2018 No Comments

This is a third post in a series dealing with very short or very long distances between atoms. Ishigaki, Shimajiri, Takeda, Katoono, and Suzuki have prepared three related analogues of hexaphenylethane that all have long C-C bonds.1 The idea is to create a core by fusing two adjacent phenyls into a naphylene, and then protect the long C-C bond through a shell made up of large aryl groups, 1. Fusing another 5-member ring opposite to the stretched C-C bond (2) creates a scissor effect that should stretch that bond further, even more so in the unsaturated version 3.

Their M062-x/6-31G* computations predict an increasing longer C-C bond (highlighted in blue in the above drawing): 1.730 Å in 1, 1.767 Å in 2, and 1.771 Å in 3. The structure of 3 is shown in Figure 3.

Figure 1. M06-2x/6-31G(d) optimized structure of 3.

These three compounds were synthesized, and characterized by IR and Raman spectroscopy. Their x-ray crystal structures at 200 K and 400K were also determined. The C-C distances are 1.742 Å (1), 1.773 Å (2) and 1.798 Å (3) with distances slightly longer at 400 K. These rank as the longest C-C bonds recorded.


1) Ishigaki, Y.; Shimajiri, T.; Takeda, T.; Katoono, R.; Suzuki, T., "Longest C–C Single Bond among Neutral Hydrocarbons with a Bond Length beyond 1.8 Å." Chem 2018, 4, 795-806, DOI: 10.1016/j.chempr.2018.01.011.


1: InChI=1S/C40H26/c1-5-17-32-27(11-1)23-24-28-12-2-6-18-33(28)39(32)36-21-9-15-31-16-10-22-37(38(31)36)40(39)34-19-7-3-13-29(34)25-26-30-14-4-8-20-35(30)40/h1-26H

2: InChI=1S/C42H28/c1-5-13-33-27(9-1)17-18-28-10-2-6-14-34(28)41(33)37-25-23-31-21-22-32-24-26-38(40(37)39(31)32)42(41)35-15-7-3-11-29(35)19-20-30-12-4-8-16-36(30)42/h1-20,23-26H,21-22H2

3: InChI=1S/C42H26/c1-5-13-33-27(9-1)17-18-28-10-2-6-14-34(28)41(33)37-25-23-31-21-22-32-24-26-38(40(37)39(31)32)42(41)35-15-7-3-11-29(35)19-20-30-12-4-8-16-36(30)42/h1-26H

Long C-C bonds are not caused by crystal packing forces

adamantane &DFT &Grimme &MP &Schreiner Steven Bachrach 25 Jun 2018 No Comments

Schreiner and Grimme have examined a few compounds (see these previous posts) with long C-C bonds that are found in congested systems where dispersion greatly aids in stabilizing the stretched bond. Their new paper1 continues this theme by examining 1 (again) and 2, using computations, and x-ray crystallography and gas-phase rotational spectroscopy and electron diffraction to establish the long C-C bond.

The distance of the long central bond in 1 is 1.647 Å (x-ray) and 1.630 Å (electron diffraction). Similarly, this distance in 2 is 1.642 Å (x-ray) and 1.632 Å (ED). These experiments discount any role for crystal packing forces in leading to the long bond.

A very nice result from the computations is that most functionals that include some dispersion correction predict the C-C distance in the optimized structures with an error of no more than 0.01 Å. (PW6B95-D3/DEF2-QZVP structures are shown in Figure 1.) Not surprisingly, HF and B3LYP without a dispersion correction predict a bond that is too long.) MP2 predicts a distance that is too short, but SCS-MP2 does a very good job.



Figure 1. PW6B95-D3/DEF2-QZVP optimized structures of 1 and 2.


1) Fokin, A. A.; Zhuk, T. S.; Blomeyer, S.; Pérez, C.; Chernish, L. V.; Pashenko, A. E.; Antony, J.; Vishnevskiy, Y. V.; Berger, R. J. F.; Grimme, S.; Logemann, C.; Schnell, M.; Mitzel, N. W.; Schreiner, P. R., "Intramolecular London Dispersion Interaction Effects on Gas-Phase and Solid-State Structures of Diamondoid Dimers." J. Am. Chem. Soc. 2017, 139, 16696-16707, DOI: 10.1021/jacs.7b07884.


1: InChI=1S/C28H38/c1-13-7-23-19-3-15-4-20(17(1)19)24(8-13)27(23,11-15)28-12-16-5-21-18-2-14(9-25(21)28)10-26(28)22(18)6-16/h13-26H,1-12H2

2: InChI=1S/C26H34O2/c1-11-3-19-15-7-13-9-25(19,21(5-11)23(27-13)17(1)15)26-10-14-8-16-18-2-12(4-20(16)26)6-22(26)24(18)28-14/h11-24H,1-10H2

An even shorter non-bonding HH distance

Uncategorized Steven Bachrach 22 May 2018 1 Comment

The competition for finding molecules with ever-closer non-bonding HH interactions is heating up. I have previously blogged about 1, a in,in-Bis(hydrosilane) designed by Pascal,1 with an HH distance of 1.57 Å, and also blogged about 2, the dimer of tri(di-t-butylphenyl)methane,2 where the distance between methine hydrogens on adjacent molecules is 1.566 Å.

Now Pascal reports on 3, which shows an even closer HH approach.3

The x-ray structure of 3 shows the in,in relationship of the two critical hydrogens, HA and HB. Though the positions of these hydrogens were refined, the C-H distance are artificially foreshortened. A variety of computed structures are reported, and these all support a very short HH non-bonding distance of about 1.52 Å. The B3PW91-D3/cc-pVTZ optimized structure is shown in Figure 1.

Figure 1. B3PW91-D3/cc-pVTZ optimized structure of 3.

The authors also note an unusual feature of the 1H NMR spectrum of 3: the HB signal appears as a double with JAB= 2.0 Hz. B3LYP/6–311++G(2df,2pd) NMR computations indicated a coupling of 3.1 Hz. This is the largest through-space coupling recorded.


1. Zong, J.; Mague, J. T.; Pascal, R. A., "Exceptional Steric Congestion in an in,in-Bis(hydrosilane)." J. Am. Chem. Soc. 2013, 135, 13235-13237, DOI: 10.1021/ja407398w.

2. Rösel, S.; Quanz, H.; Logemann, C.; Becker, J.; Mossou, E.; Cañadillas-Delgado, L.; Caldeweyher, E.; Grimme, S.; Schreiner, P. R., "London Dispersion Enables the Shortest Intermolecular Hydrocarbon H···H Contact." J. Am. Chem. Soc. 2017, 139, 7428–7431, DOI: 10.1021/jacs.7b01879.

3. Xiao, Y.; Mague, J. T.; Pascal, R. A., "An Exceptionally Close, Non-Bonded Hydrogen–Hydrogen Contact with Strong Through-Space Spin–Spin Coupling." Angew. Chem. Int. Ed. 2018, 57, 2244-2247, DOI: 10.1002/anie.201712304.


3: InChI=1S/C27H24S3/c1-4-17-13-28-10-16-11-29-14-18-5-2-8-21-24(18)27-23(17)20(7-1)26(21)22-9-3-6-19(25(22)27)15-30-12-16/h1-9,16,26-27H,10-15H2

MD studies of simple pericyclic reactions

Cope Rearrangement &Diels-Alder &Dynamics &Houk Steven Bachrach 07 May 2018 No Comments

At the recent ACS meeting in New Orleans, Ken Houk spoke at the Dreyfus award session in honor of Michele Parrinello. Ken’s talk included discussion of some recent molecular dynamics studies of pericyclic reactions. Because of their similarities in approaches and observations, I will discuss three recent papers from his group (which Ken discussed in New Orleans) in this post.

The Cope rearrangement, a fundamental organic reaction, has been studied extensively by computational means (see Chapter 4.2 of my book). Mackey, Yang, and Houk examine the degenerate Cope rearrangement of 1,5-hexadiene with molecular dynamics at the (U)B3LYP/6-31G(d) level.1 They examined 230 trajectories, and find that of the 95% of them that are reactive, 94% are trajectories that directly cross through the transition zone. By this, Houk means that the time gap between the breaking and forming C-C bonds is less than 60 fs, the time for one C-C bond vibration. The average time in the transition zone is 35 fs. This can be thought of as “dynamically concerted”. For the other few trajectories, a transient diradical with lifetime of about 100 fs is found.

The dimerization of cyclopentadiene finds the two [4+2] pathways merging into a single bispericylic transition state. 2 Only a small minority (13%) of the trajectories sample the region about the Cope rearrangement that interconverts the two mirror image dimers. These trajectories average about 60 fs in this space, which comes from the time separation between the formation of the two new C-C bonds. The majority of the trajectories quickly pass through the dimerization transition zone in about 18 fs, and avoid the Cope TS region entirely. These paths can be thought of as “dynamically concerted”, while the other set of trajectories are “dynamically stepwise”. It should be noted however that the value of S2 in the Cope transition zone are zero and so no radicals are being formed.

Finally, Yang, Dong, Yu, Yu, Li, Jamieson, and Houk examined 15 different reactions that involve ambimodal (i.e. bispericyclic) transition states.3 They find a strong correlation between the differences in the bond lengths of the two possible new bond vs. their product distribution. So for example, in the reaction shown in Scheme 1, bond a is the one farthest along to forming. Bond b is slightly shorter than bond c. Which of these two is formed next is dependent on the dynamics, and it turns out the Pab is formed from 73% of the trajectories while Pac is formed only 23% of the time. This trend is seen across the 15 reaction, namely the shorter of bond b or c in the transition state leads to the larger product formation. When competing reactions involve bonds with differing elements, then a correlation can be found with bond order instead of with bond length.

Scheme 1


1) Mackey, J. L.; Yang, Z.; Houk, K. N., "Dynamically concerted and stepwise trajectories of the Cope rearrangement of 1,5-hexadiene." Chem. Phys. Lett. 2017, 683, 253-257, DOI: 10.1016/j.cplett.2017.03.011.

2) Yang, Z.; Zou, L.; Yu, Y.; Liu, F.; Dong, X.; Houk, K. N., "Molecular dynamics of the two-stage mechanism of cyclopentadiene dimerization: concerted or stepwise?" Chem. Phys. 2018, in press, DOI: 10.1016/j.chemphys.2018.02.020.

3) Yang, Z.; Dong, X.; Yu, Y.; Yu, P.; Li, Y.; Jamieson, C.; Houk, K. N., "Relationships between Product Ratios in Ambimodal Pericyclic Reactions and Bond Lengths in Transition Structures." J. Am. Chem. Soc. 2018, 140, 3061-3067, DOI: 10.1021/jacs.7b13562.

The structure of gauche-1,3-butadiene

Tunneling Steven Bachrach 24 Apr 2018 1 Comment

Sometimes you run across a paper that is surprising for a strange reason: hasn’t this work been done years before? That was my response to seeing this paper on the structure of gauche-1,3-butadiene.1 Surely, a molecule as simple as this has been examined to death. But, in fact there has been some controversy over whether the cis or gauche form is the second lowest energy conformation. Computations have indicated that the cis form is a transition state for interconverting the two gauche isomers, but experimental confirmation was probably so late in coming due to the small amount of the gauche form present and its small dipole moment.

This paper describes Fourier-transform microwave (FTMW) spectroscopy using two variants: cavity-enhanced FTMW combined with a supersonic expansion and chirped-pulse FTMW in a cryogenic buffer gas cell. In addition, computations were done at CCSD(T) using cc-pCVTZ through cc-pCV5Z basis sets and corrections for perturbative quadruples. The computed structure is shown in Figure 1. In addition to confirming this non-planar structure, with a C-C-C-C dihedral angle of 33.8°, they demonstrate the tunneling between the two mirror image gauche conformations, through the cis transition state.

Figure 1. Computed geometry of gauche-1,3-butadiene.


1. Baraban, J. H.; Martin-Drumel, M.-A.; Changala, P. B.; Eibenberger, S.; Nava, M.; Patterson, D.; Stanton, J. F.; Ellison, G. B.; McCarthy, M. C., "The Molecular Structure of gauche-1,3-Butadiene: Experimental Establishment of Non-planarity." Angew. Chem. Int. Ed. 2018, 57, 1821-1825, DOI: 10.1002/anie.201709966.


1,3-butadiene: InChI=1S/C4H6/c1-3-4-2/h3-4H,1-2H2

quintuple helicene fused corannulene

Aromaticity Steven Bachrach 09 Apr 2018 No Comments

Corannulene 1 is an interesting aromatic compound because it is nonplanar, having a bowl shape. [6]helicene is an interesting aromatic compound because it is nonplanar, having the shape of a helix. Kato, Segawa, Scott and Itami have joined these together to synthesize the interesting quintuple helicene compound 3.1

The optimized structure of 3 is shown in Figure 1. They utilized computations to corroborate two experimental findings. First, the NMR spectra of 3 shows a small number of signals indicating that the bowl inversion should be rapid. The molecule has C5 symmetry due to the bowl shape of the corannulene core. Rapid inversion makes the molecule effectively D5. (The inversion transition state is of D5 symmetry, and would be a nice quiz question for those looking for molecules of unusual point groups.) The B3LYP/6-31G(d) computed bowl inversion barrier is only 1.9 kcal mol-1, significantly less that the bowl inversion barrier of 1: 10.4 kcal mol-1. This reduction is partly due to the shallower bowl depth of 3 (0.572 Å in the x-ray structure, 0.325 Å in the computed structure) than in 1 (0.87 Å).

Figure 1. Optimized structure of 3.

Second, they took the enhanced MMMMM-isomer and heated it to obtain the thermodynamic properties for the inversion to the PPPPP-isomer. (The PPPPP-isomer is shown in the top scheme.) The experimental values are ΔH = 36.8 kcal mol-1, ΔS = 8.7 cal mol-1 K-1, and ΔG = 34.2 kcal mol-1 at 298 K. They computed all of the stereoisomers of 3 along with the transition states connecting them. The largest barrier is found in going from MMMMM3 to MMMMP3 with a computed barrier of 34.5 kcal mol-1, in nice agreement with experiment.


1. Kato, K.; Segawa, Y.; Scott, L. T.; Itami, K., "A Quintuple [6]Helicene with a Corannulene Core as a C5-Symmetric Propeller-Shaped π-System." Angew. Chem. Int. Ed. 2018, 57, 1337-1341, DOI: 10.1002/anie.201711985.


1: InChI=1S/C20H10/c1-2-12-5-6-14-9-10-15-8-7-13-4-3-11(1)16-17(12)19(14)20(15)18(13)16/h1-10H

2: InChI=1S/C26H16/c1-3-7-22-17(5-1)9-11-19-13-15-21-16-14-20-12-10-18-6-2-4-8-23(18)25(20)26(21)24(19)22/h1-16H

3: InChI=1S/C80H40/c1-11-31-51-41(21-1)42-22-2-12-32-52(42)62-61(51)71-63-53-33-13-3-23-43(53)44-24-4-14-34-54(44)64(63)73-67-57-37-17-7-27-47(57)48-28-8-18-38-58(48)68(67)75-70-60-40-20-10-30-50(60)49-29-9-19-39-59(49)69(70)74-66-56-36-16-6-26-46(56)45-25-5-15-35-55(45)65(66)72(62)77-76(71)78(73)80(75)79(74)77/h1-40H

Computed spectra and the structure of (+)-frondosin B

Optical Rotation Steven Bachrach 26 Mar 2018 No Comments

The structure of (+)-frondosin B 1 has been the subject of some concern. The compound has been synthesized by a number of research groups with the expected R isomer as the target. However, the Danishefsky1 and MacMillan2 synthesis led to a molecule with [α]D of about +16°, while Trauner3 reports a value of -16.8° and Ovaska4 prepared the S isomer with [α]D = -17.3°. Something is amiss here.

Joyce and coworkers have looked into this structure problem through a combination of advanced analytical techniques and computational chemistry.5 They utilize optical activity, electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) and compare the experiments with computational results. IR and VCD were computed at B3LYP/6-31G** using a Boltzmann-weighted set of low-energy conformations. ECD computations were done at CAM-B3LYP/6-31++G**//B3LYP/6-31G**.

Basically, they found that (+)-frondosin B does have the R stereocenter. The different synthetic schemes did actually all lead to the same isomer, tested by looking at key intermediates along the way. The discrepancy in the optical activity is due to a small impurity, 2, that has the opposite rotation and a magnitude 10 times greater than that of authentic 1.

This paper is another nice example demonstrating the power of modern computational approaches to spectra that can be extremely valuable in structure determination. Organic chemists of all stripes should certainly be aware of how this tool can complement experiments.

My thanks to Derek Lowe who posted on this paper in his In The Pipeline blog.


1) Inoue, M.; Carson, M. W.; Frontier, A. J.; Danishefsky, S. J., "Total Synthesis and Determination of the Absolute Configuration of Frondosin B." J. Am. Chem. Soc.
2001, 123, 1878-1889, DOI: 10.1021/ja0021060.

2) Reiter, M.; Torssell, S.; Lee, S.; MacMillan, D. W. C., "The organocatalytic three-step total synthesis of (+)-frondosin B." Chem. Sci. 2010, 1, 37-42, DOI: 10.1039/C0SC00204F.

3) Hughes, C. C.; Trauner, D., "Palladium-catalyzed couplings to nucleophilic heteroarenes: the total synthesis of (−)-frondosin B." Tetrahedron 2004, 60, 9675-9686, DOI: 10.1016/j.tet.2004.07.041.

4) Ovaska, T. V.; Sullivan, J. A.; Ovaska, S. I.; Winegrad, J. B.; Fair, J. D., "Asymmetric Synthesis of Seven-Membered Carbocyclic Rings via a Sequential Oxyanionic 5-Exo-Dig Cyclization/Claisen Rearrangement Process. Total Synthesis of (−)-Frondosin B." Org. Letters 2009, 11, 2715-2718, DOI: 10.1021/ol900967j.

5) Joyce, L. A.; Nawrat, C. C.; Sherer, E. C.; Biba, M.; Brunskill, A.; Martin, G. E.; Cohen, R. D.; Davies, I. W., "Beyond optical rotation: what’s left is not always right in total synthesis." Chem. Sci. 2018, 9, 415-424, DOI: 10.1039/C7SC04249C.


1: InChI=1S/C20H24O2/c1-12-6-8-16-14(5-4-10-20(16,2)3)18-15-11-13(21)7-9-17(15)22-19(12)18/h7,9,11-12,21H,4-6,8,10H2,1-3H3/t12-/m1/s1

2: InChI=1S/C20H24O2/c1-12-5-4-10-20(3)16(12)8-6-13(2)19-18(20)15-11-14(21)7-9-17(15)22-19/h7,9,11,13,21H,4-6,8,10H2,1-3H3/t13-,20-/m1/s1

C60 Fullerene isomers

fullerene &Grimme Steven Bachrach 05 Mar 2018 No Comments

The Grimme group has examined all 1812 C60 isomers, in part to benchmark some computational methods.1 They computed all of these structures at PW6B95-D3/def2-QZVP//PBE-D3/def2-TZVP. The lowest energy structure is the expected fullerene 1 and the highest energy structure is the nanorod 2 (see Figure 1).



Figure 1. Optimized structures of the lowest (1) and highest (2) energy C60 isomers.

About 70% of the isomers like in the range of 150-250 kcal mol-1 above the fullerene 1, and the highest energy isomer 2 lies 549.1 kcal mol-1 above 1. To benchmark some computational methods, they selected the five lowest energy isomers and five other isomers with higher energy to serve as a new database (C60ISO), with energies computed at DLPNO-CCSD(T)/CBS*. The mean absolute deviation of the PBE-D3/def2-TZVP relative energies with the DLPNO-CCSD(T)/CBS* energies is relative large 10.7 kcal mol-1. However, the PW6B95-D3/def2-QZVP//PBE-D3/def2-TZVP method is considerably better, with a MAD of only 1.7 kcal mol-1. This is clearly a reasonable compromise method for fullerene-like systems, balancing accuracy with computational time.

They also compared the relative energies of all 1812 isomers computed at PW6B95-D3/def2-QZVP//PBE-D3/def2-TZVP with a number of semi-empirical methods. The best results are with the DFTB-D3 method, with an MAD of 5.3 kcal mol-1.


1) Sure, R.; Hansen, A.; Schwerdtfeger, P.; Grimme, S., "Comprehensive theoretical study of all 1812 C60 isomers." Phys. Chem. Chem. Phys. 2017, 19, 14296-14305, DOI: 10.1039/C7CP00735C.


1: InChI=1S/C60/c1-2-5-6-3(1)8-12-10-4(1)9-11-7(2)17-21-13(5)23-24-14(6)22-18(8)28-20(12)30-26-16(10)15(9)25-29-19(11)27(17)37-41-31(21)33(23)43-44-34(24)32(22)42-38(28)48-40(30)46-36(26)35(25)45-39(29)47(37)55-49(41)51(43)57-52(44)50(42)56(48)59-54(46)53(45)58(55)60(57)59

2: InChI=1S/C60/c1-11-12-2-21(1)31-41-32-22(1)3-13(11)15-5-24(3)34-43(32)53-55-47-36-26-6-16-17-7(26)28-9-19(17)20-10-29-8(18(16)20)27(6)37-46(36)54(51(41)55)52-42(31)33-23(2)4(14(12)15)25(5)35-44(33)58-56(52)48(37)39(29)50-40(30(9)10)49(38(28)47)57(53)59(45(34)35)60(50)58

Strain-promoted cycloaddition to cyclooctyne

cycloadditions &DFT &Diels-Alder Steven Bachrach 19 Feb 2018 No Comments

Click chemistry has been used in a broad range of applications. The use of metal catalysts has limited its application to biological system, but the development of strain-promoted cycloaddition to cyclooctyne has opened up click chemistry to bioorthogonal labeling.

An interesting variation on this is the use of 1,2-benzoquinone 1 and substituted analogues as the Diels-Alder diene component. Escorihuela and co-workers have reported on the use of this diene with a number of cyclooctyne derivatives, measuring kinetics and also using computations to assess the mechanism.1

Their computations focused on two reactions using cyclooctyne 2 and the cyclopropane-fused analogue 3:

Reaction 1

Reaction 2

They examined these reactions with a variety of density functionals along with some post-HF methods. The transition states of the two reactions are shown in Figure 1. A variety of different density functionals and MP2 are consistent in finding synchronous or nearly synchronous transition states.



Figure 1. B97D/6-311+G(d,p) transition states for Reactions 1 and 2.

In terms of activation energies, all of the DFT methods consistently overestimate the barrier by about 5-10 kcal mol-1, with B97D-D3 doing the best. MP2 drastically underestimates the barriers, though the SOS-MP2 or SCS-MP2 improve the estimate. Both CCSD(T) and MR-AQCC provide estimates of about 8.5 kcal mol-1, still 3-4 kcal mol-1 too high. The agreement between CCSD(T), a single reference method, and MR-AQCC, a multireference method, indicate that the transition states have little multireference character. Given the reasonable estimate of the barrier afforded by B97D-D3, and its tremendous performance advantage over SCS-MP2, CCSD(T) and MR-AQCC, this is the preferred method (at least with current technology) for examining Diels-Alder reactions like these, especially with larger molecules.


1) Escorihuela, J.; Das, A.; Looijen, W. J. E.; van Delft, F. L.; Aquino, A. J. A.; Lischka, H.; Zuilhof, H., "Kinetics of the Strain-Promoted Oxidation-Controlled Cycloalkyne-1,2-quinone Cycloaddition: Experimental and Theoretical Studies." J. Org. Chem. 2018, 83, 244-252, DOI: 10.1021/acs.joc.7b02614.


1: InChI=1S/C6H4O2/c7-5-3-1-2-4-6(5)8/h1-4H

2: InChI=1S/C8H12/c1-2-4-6-8-7-5-3-1/h1-6H2

3: InChI=1S/C9H12/c1-2-4-6-9-7-8(9)5-3-1/h8-9H,3-7H2

4: InChI=1S/C14H16O2/c15-13-11-7-8-12(14(13)16)10-6-4-2-1-3-5-9(10)11/h7-8,11-12H,1-6H2

5: InChI=1S/C15H16O2/c16-14-12-5-6-13(15(14)17)11-4-2-9-7-8(9)1-3-10(11)12/h5-6,8-9,12-13H,1-4,7H2/t8-,9+,12?,13?

New Procedure for computing NMR spectra with spin-spin coupling

Grimme &NMR Steven Bachrach 05 Feb 2018 No Comments

Computed NMR spectra have become a very useful tool in identifying chemical structures. I have blogged on this multiple times. A recent trend has been the development of computational procedures that lead to computed spectra (again, see that above link). Now, Grimme, Neese and coworkers have offered their approach to computed NMR spectra, including spin-spin splitting.1

Their procedure involves four distinct steps.

  1. Generation of the conformer and rotamer space. This is a critical distinctive element of their method in that they take a number of different tacks for sampling conformational space to insure that they have identified all low-energy structures. This involves a combination of normal mode following, genetic structure crossing (based on genetic algorithms for optimization), and molecular dynamics. Making this all work is their choice of using the computational efficient GFN-xTB2 quantum mechanical method.
  2. The low-energy structures are then subjected to re-optimization at PBEh-3c and then single-point energies obtained at DSD-BLYP-D3/def2-TZVPP including treatment of solvation by COSMO-RS. The low-energy structures that contribute 4% or more of the Boltzmann-weighted population are then carried forward.
  3. Chemical shifts and spin-spin coupling constants are then computed with the PBE0 method and the pcS and pcJ basis sets developed by Jensen for computing NMR shifts.3
  4. Lastly, the chemical shifts and coupling constants are averaged and the spin Hamiltonian is solved.

The paper provides a number of examples of the application of the methodology, all with quite good success. The computer codes to run this method are available for academic use from


1) Grimme, S.; Bannwarth, C.; Dohm, S.; Hansen, A.; Pisarek, J.; Pracht, P.; Seibert, J.; Neese, F., "Fully Automated Quantum-Chemistry-Based Computation of Spin–Spin-Coupled Nuclear Magnetic Resonance Spectra." Angew. Chem. Int. Ed. 2017, 56, 14763-14769, DOI: 10.1002/anie.201708266.

2) Grimme, S.; Bannwarth, C.; Shushkov, P., "A Robust and Accurate Tight-Binding Quantum Chemical Method for Structures, Vibrational Frequencies, and Noncovalent Interactions of Large Molecular Systems Parametrized for All spd-Block Elements (Z = 1–86)." J. Chem. Theory Comput. 2017, 13, 1989-2009, DOI: 10.1021/acs.jctc.7b00118.

3) Jensen, F., "Basis Set Convergence of Nuclear Magnetic Shielding Constants Calculated by Density Functional Methods." J. Chem. Theory Comput. 2008, 4, 719-727, DOI: 10.1021/ct800013z.

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