Archive for the 'NMR' Category

Dynamic effects in computing NMR (and a patent issue?)

The prediction of NMR chemical shifts and coupling constants through ab initio computation is a major development of the past decade in computational organic chemistry. I have written about many developments on this blog. An oft-used method is a linear scaling of the computed chemical shifts to match those of some test set. Kwan and Liu wondered if the dynamics of molecular motions might be why we need this correction.1

They suggest that the chemical shift can be computed as

<σ> = σ(static molecule using high level computation) + error

where the error is the obtained by using a low level computation taking the difference between the chemical shifts obtained on a dynamic molecule less that obtained with a static molecule. The dynamic system is obtained by performing molecular dynamics of the molecule, following 25 trajectories and sampling every eighth point.

They find outstanding agreement for the proton chemical shift of 12 simple molecules (mean error of 0.02 ppm) and the carbon chemical shift of 19 simple molecules (mean error of 0.5 ppm) without any scaling. Similar excellent agreement is found for a test set of natural products.

They finish up with a discussion of [18]annulene 1. The structure of 1 is controversial. X-ray crystallography indicates a near D6h geometry, but the computed NMR shifts using a D6h geometry are in dramatic disagreement with the experimental values, leading Schleyer to suggest a C2  geometry. Kwan and Liu applied their dynamic NMR method to the D6h, D3h, and C2 structures, and find the best agreement with the experimental chemical shifts are from the dynamic NMR initiated from the D6h geometry. Dynamic effects thus make up for the gross error found with the static geometry, and now bring the experimental and computational data into accord.

One final note on this paper. The authors indicate that they have filed a provisional patent on their method. I am disturbed by this concept of patenting a computational methodology, especially in light of the fact that many other methods have been made available to the world without any legal restriction. For example, full details including scripts to apply Tantillo’s correction method are available through the Cheshire site and a web app to implement Goodman’s DP4 method are available for free. Provisional patents are not available for review from the US Patent Office so I cannot assess just what is being protected here. However, I believe that this action poses a real concern over the free and ready exchange of computational methodologies and ideas.


(1) Kwan, E. E.; Liu, R. Y. "Enhancing NMR Prediction for Organic Compounds Using Molecular Dynamics," J. Chem. Theor. Comput. 2015, 11, 5083-5089, DOI: 10.1021/acs.jctc.5b00856.


1: InChI=1S/C18H18/c1-2-4-6-8-10-12-14-16-18-17-15-13-11-9-7-5-3-1/h1-18H/b2-1-,3-1+,4-2+,5-3+,6-4+,7-5-,8-6-,9-7+,10-8+,11-9+,12-10+,13-11-,14-12-,15-13+,16-14+,17-15+,18-16+,18-17-

NMR Steven Bachrach 11 Jan 2016 2 Comments

Structure revision: Vescalagin and Castalagin

Vescalagin 1 and castalagin 2 are found in plants and also in wine and whisky. They possess some intriguing stereochemistry and the topic of interest in the paper by Tanaka and coworkers is the stereochemistry of the triphenyl fragment.1 The original proposed structure indicated a (S,S) (1a and 2a) configuration, yet a molecular mechanics study suggest the (S,R) (1b and 2b) configuration would be lower in energy.

1a: R1 = OH, R2 = H
2a: R1 = H, R2 = OH

1b: R1 = OH, R2 = H
2b: R1 = H, R2 = OH

Recognizing the power of DFT computations in resolving this type of structural problem, Tanaka measured the ECD spectrum of the hydrolyzed forms of 1 and 2, namely 3 and 4. The (S,S) and (S,R) isomers of 3 and 4 were subjected to a Monte Carlo search using MM. Low-lying conformers were reoptimized at B3LYP/6-31G(d,p) including PCM, modeling methanol as the solvent. The ECD spectrum was then predicted using all conformations with a population over 1%. The computed spectrum for the (S,R) isomer reproduced the negative Cotton effect at 218 nm observed in the experiment.

3a: R1 = OH, R2 = H
4a: R1 = H, R2 = OH

3b: R1 = OH, R2 = H
3b: R1 = H, R2 = OH

The structures of 1 and 2 of both stereoisomers were next optimized at B3LYP/6-31G(d,p) including PCM. The lowest energy conformation of each is shown in Figure 1. The 1H and 13C chemical shifts were computed at this level, again using all conformations with a population greater than 1%. The correlation coefficient for the fit between the experimental values of the chemical shifts and 1a and 2a are significantly lower for both proton and carbon, while the correlation coefficients compared to 1b and 2b are larger, 0.93 or better. Therefore, the structures of vescalagin is 1b and castalagin is 2b.



Figure 1. B3LYP/6-31G(d,p) optimized geometries of the lowest energy conformers of 1b and 2b.


(1) Matsuo, Y.; Wakamatsu, H.; Omar, M.; Tanaka, T. "Reinvestigation of the Stereochemistry of the C-Glycosidic Ellagitannins, Vescalagin and Castalagin," Org. Lett. 2014, 17, 46-49, DOI: 10.1021/ol503212v.


1: InChI=1S/C41H26O26/c42-8-1-5-12(24(48)21(8)45)13-6(2-9(43)22(46)25(13)49)39(60)65-34-11(4-63-37(5)58)64-38(59)7-3-10(44)23(47)26(50)14(7)15-18-16(28(52)32(56)27(15)51)17-19-20(30(54)33(57)29(17)53)31(55)35(66-41(19)62)36(34)67-40(18)61/h1-3,11,31,34-36,42-57H,4H2/t11-,31-,34+,35+,36-/m0/s1

2: InChI=1S/C41H26O26/c42-8-1-5-12(24(48)21(8)45)13-6(2-9(43)22(46)25(13)49)39(60)65-34-11(4-63-37(5)58)64-38(59)7-3-10(44)23(47)26(50)14(7)15-18-16(28(52)32(56)27(15)51)17-19-20(30(54)33(57)29(17)53)31(55)35(66-41(19)62)36(34)67-40(18)61/h1-3,11,31,34-36,42-57H,4H2/t11-,31+,34+,35+,36-/m0/s1

NMR Steven Bachrach 09 Mar 2015 No Comments

Structures of cephalosporolide C, J, and bassianolone

Here is a story that must drive chemical database quality control personnel nuts. Song, et al. noticed that the reported 13C NMR of the natural products cephalosporolide C 1, cephalosporolide J 2 and bassianolone 3 are identical.1 Given that it is highly unlikely that two diastereomers would have identical NMR spectra, the likelihood that these three have identical spectra seemed remote at best.

Compounds 1 and 2 were synthesized and their structures confirmed by x-ray crystallography. Their 13C NMR spectra show clear distinctions, indicating that the isolated “2” is actually 1. Experimental support for the notion that 1 and 3 are actually the same was provided by preparing the diacetylide of 1 and comparing its NMR spectra to that of natural “3”.

Quantum computations confirmed that in fact the natural product thought to be 3 is actually 1. The structures of 1 and 3 were optimized at B3LYP/6-311+G(2d,p) and 13C chemical shifts were computed with these geometries at mPW1PW91/6-311+G(2d,p)/CPCM(chloroform). (The computed structures are shown in Figure 1.) The mean absolute deviation (MAD) between the computed and experimental spectra for 1 is 0.97 ppm, while the MAD for the computed spectrum of 3 compared with the experimental values is 2.44 ppm, with a maximum error of 5.13ppm, more than twice the maximum error with structure 1. The authors attribute the misassignments to a faulty initial spectra of authentic cephalosporolide C 1.



Figure 1. B3LYP/6-311+G(2d,p) optimized geometries of 1 and 3.


(1) Song, L.; Lee, K.-H.; Lin, Z.; Tong, R. "Structural Revision of Cephalosporolide J and Bassianolone," J. Org. Chem. 2014, 79, 1493-1497, DOI: 10.1021/jo402602h.


1: InChI=1S/C10H16O5/c1-6-2-3-7(11)4-8(12)9(13)5-10(14)15-6/h6,8-9,12-13H,2-5H2,1H3/t6-,8+,9+/m1/s1

2: InChI=1S/C10H16O5/c1-6-2-3-7(11)4-8(12)9(13)5-10(14)15-6/h6,8-9,12-13H,2-5H2,1H3/t6-,8+,9-/m1/s1

3: InChI=1S/C10H16O5/c1-6(11)2-3-7(12)4-9-8(13)5-10(14)15-9/h6,8-9,11,13H,2-5H2,1H3/t6-,8+,9+/m1/s1

NMR Steven Bachrach 16 Feb 2015 No Comments

Protocol for computing NMR chemical shifts

I have posted on the use of computed NMR chemical shifts and coupling constants to help aid in structure identification. The second edition of my book Computational Organic Chemistry has a largely all-new chapter on structure identification aided by computed spectra, especially NMR spectra. In my recent opinion piece speculating on challenges in computational organic chemistry,1 the first area I highlight is encouraging the larger use of computed spectra as an essential component of structure determination.

While more and more non-traditional computational users are employing quantum computations towards these problems, I suspect that many non-users are a bit wary about stepping into an arena they are not expert in, an arena chock-filled with acronyms and methods and potentially little guidance. While some very nice papers2-6 and web sites (Chemical Shift Repository (Cheshire) and DP4) do outline procedures for using computations in this fashion, they are not truly designed for the non-specialist.

Well, fear not any longer. Hoye and coworkers, synthetic chemists who have utilized computational approaches in structure determinations for a number of years, have written a detailed step-by-step protocol for using a standard computational approach towards structure determination.7 The article is written with the synthetic chemist in mind, and includes a number of scripts to automate many of the steps.

For the specialist, the overall outline of the protocol is fairly routine:

  1. Utilize MacroModel to perform a conformational search for each proposed structure, retaining the geometries within 5 kcal mol-1 of the global minimum.
  2. Optimize these conformations for each structure at M06-2x/6-31+G(d).
  3. For each conformation of each structure, compute the 1H and 13C chemical shifts, scale them, and determine the Boltzmann weighted chemical shifts
  4. Compare these chemical shifts with the experimental values using Mean Absolute Error

The article is straightforward and easily guides the novice user through these steps. Anyone unsure of how to utilize quantum chemical computations in structure determination is well advised to start with this article.


(1) Bachrach, S. M. "Challenges in computational organic chemistry," WIRES: Comput. Mol. Sci. 2014, 4, 482-487, DOI: 10.1002/wcms.1185.

(2) Lodewyk, M. W.; Siebert, M. R.; Tantillo, D. J. "Computational Prediction of 1H and 13C Chemical Shifts: A Useful Tool for Natural Product, Mechanistic, and Synthetic Organic Chemistry," Chem. Rev. 2012, 112, 1839–1862, DOI: 10.1021/cr200106v.

(3) Bally, T.; Rablen, P. R. "Quantum-Chemical Simulation of 1H NMR Spectra. 2. Comparison of DFT-Based Procedures for Computing Proton-Proton Coupling Constants in Organic Molecules," J. Org. Chem. 2011, 76, 4818-4830, DOI: 10.1021/jo200513q.>

(4) Jain, R.; Bally, T.; Rablen, P. R. "Calculating Accurate Proton Chemical Shifts of Organic Molecules with Density Functional Methods and Modest Basis Sets," J. Org. Chem. 2009, 74, 4017-4023, DOI: 10.1021/jo900482q.

(5) Smith, S. G.; Goodman, J. M. "Assigning the Stereochemistry of Pairs of Diastereoisomers Using GIAO NMR Shift Calculation," J. Org. Chem. 2009, 74, 4597-4607, DOI: 10.1021/jo900408d.

(6) Smith, S. G.; Goodman, J. M. "Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability," J. Am. Chem. Soc. 2010, 132, 12946-12959, DOI: 10.1021/ja105035r.

(7) Willoughby, P. H.; Jansma, M. J.; Hoye, T. R. "A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts," Nat. Protocols 2014, 9, 643-660, DOI: 10.1038/nprot.2014.042.

NMR Steven Bachrach 09 Feb 2015 No Comments

Structure of Citrinalin B

Here is another nice example of the partnership between experiment and computation in ascertaining molecular structure. The Sarpong, Tantillo, Andersen, Berlinck, and Miller groups collaborated on the synthesis, characterization and biosynthesis of some metabolites from Penniculium strains.1 I will focus here on just the structural identification component of this paper; the synthesis and the biosynthesis are very interesting too!

Cyclopiamine A 1 and cyclopiamine B 2 interconvert through an intermediate that allows for the epimerization at carbon bearing the nitro group.2



Citrinalin A 3 might also seem to undergo the same type of ring opening-ring closing reaction to produce citrinalin B. However, the original proposed structure3 of citrinalin B 4 implies an epimerization at a different carbon (at the ring fusion to the terminal 5 member ring). These authors suggested that perhaps the proper structure of citrinalin B is 5, which differs from citrinalin A only at the carbon bearing the nitro group, analogous to the relationship between 1 and 2.




The low energy conformations of both 4 and 5 (actually the trifluoroacetic acid salts) were optimized at B3LYP/6-31+G(d,p) and the chemical shifts for both 1H and 13C were computed, Boltzmann-weighted and scaled, and then compared with the NMR spectra of authentic citrinalin B. (The lowest energy conformations of 4 and 5 are shown in Figure 1.) The corrected mean absolute deviations for the 1H and 13C chemical shift for the original structure 4 are 0.45 ppm and 2.0 ppm, respectively (with the largest outliers of 2.3 ppm for H and 9.6 ppm for C). These errors are about twice what is observed in comparing the experimental and computed 1H and 13C chemical shifts of 3. The agreement between the computed and experimental values using 5 are much improved, with mean deviations of 0.12 and 1.6ppm, and largest deviations of 0.38 ppm for 1H and 4.4 ppm for 13C. Use of Goodman’s DP4 method indicates a 100% probability that the structure of citrinalin B is 5. This prediction is confirmed by the x-ray structure.



Figure 1. B3LYP/6-31+G(d,p) optimized lowest energy conformers of 4 and 5.


(1) Mercado-Marin, E. V.; Garcia-Reynaga, P.; Romminger, S.; Pimenta, E. F.; Romney, D. K.; Lodewyk, M. W.; Williams, D. E.; Andersen, R. J.; Miller, S. J.; Tantillo, D. J.; Berlinck, R. G. S.; Sarpong, R. "Total synthesis and isolation of citrinalin and cyclopiamine congeners," Nature 2014, 509, 318-324, DOI: 10.1038/nature13273.

(2) Bond, R. F.; Boeyens, J. C. A.; Holzapfel, C. W.; Steyn, P. S. "Cyclopiamines A and B, novel oxindole metabolites of Penicillium cyclopium westling," J. Chem. Soc., Perkin Trans I 1979, 1751-1761, DOI: 10.1039/P19790001751.

(3) Pimenta, E. F.; Vita-Marques, A. M.; Tininis, A.; Seleghim, M. H. R.; Sette, L. D.; Veloso, K.; Ferreira, A. G.; Williams, D. E.; Patrick, B. O.; Dalisay, D. S.; Andersen, R. J.; Berlinck, R. G. S. "Use of Experimental Design for the Optimization of the Production of New Secondary Metabolites by Two Penicillium Species," J. Nat. Prod. 2010, 73, 1821-1832, DOI: 10.1021/np100470h.


1: InChI=1S/C26H33N3O5/c1-23(2)12-17(30)20-18(34-5)9-8-16-21(20)28(23)22(31)26(16)13-25(29(32)33)14-27-10-6-7-15(27)11-19(25)24(26,3)4/h8-9,15,19H,6-7,10-14H2,1-5H3/t15-,19+,25+,26-/m1/s1

2: InChI=1S/C26H33N3O5/c1-23(2)12-17(30)20-18(34-5)9-8-16-21(20)28(23)22(31)26(16)13-25(29(32)33)14-27-10-6-7-15(27)11-19(25)24(26,3)4/h8-9,15,19H,6-7,10-14H2,1-5H3/t15-,19+,25-,26-/m1/s1

3: InChI=1S/C25H31N3O5/c1-22(2)11-16(29)19-17(33-22)8-7-15-20(19)26-21(30)25(15)12-24(28(31)32)13-27-9-5-6-14(27)10-18(24)23(25,3)4/h7-8,14,18H,5-6,9-13H2,1-4H3,(H,26,30)/t14-,18+,24+,25-/m0/s1

4: InChI=1S/C25H31N3O5/c1-22(2)11-16(29)19-17(33-22)8-7-15-20(19)26-21(30)25(15)12-24(28(31)32)13-27-9-5-6-14(27)10-18(24)23(25,3)4/h7-8,14,18H,5-6,9-13H2,1-4H3,(H,26,30)/t14-,18-,24-,25+/m1/s1

5: InChI=1S/C25H31N3O5/c1-22(2)11-16(29)19-17(33-22)8-7-15-20(19)26-21(30)25(15)12-24(28(31)32)13-27-9-5-6-14(27)10-18(24)23(25,3)4/h7-8,14,18H,5-6,9-13H2,1-4H3,(H,26,30)/t14-,18+,24-,25-/m0/s1

NMR Steven Bachrach 24 Jun 2014 4 Comments

Structure determination: Quercusnin A

Here’s another nice example of the use of computed NMR spectra to aid in structure identification. Quercusnin A was identified in an extract of dried sapwood from the oak tree Quercus crispula. The NMR sectrum along with structural comparison to the previously determined extract vescalagin, led the authors to the structure 1.1


To aid in determining the absolute stereochemistry as centers 1’ and A8, the authors employed a computational approach. Conformers of the four diastereomers (RR, RS, SR, SS) were optimized first with molecular mechanics, then the low energy conformers were reoptimized at AM1, and then finally all of the conformers within 6 kcal mol-1 of the lowest energy structure were reoptimized at PCM(acetone)/B3LYP/6-31G(d,p). The 1H and 13C NMR chemical shifts for all of the structures that contribute greater than 1% to the Boltzmann population were computed at PCM(acetone)mPW1PW91/6-311+G(2d,p)//B3LYP/6-31G(d,p). The DP4 probability (see this post) identified the (1’S,A8R) isomer with 100% probability for matching up with the experimental NMR spectrum. Additionally, the computed ECD spectrum matches nicely with the experimental spectra for this same stereoisomer. The lowest energy conformer of 1 is shown in Figure 1.


Figure 1. PCM(acetone)/B3LYP/6-31G(d,p) structure of the lowest energy conformer of 1.


(1) Omar, M.; Matsuo, Y.; Maeda, H.; Saito, Y.; Tanaka, T. "New Metabolites of C-Glycosidic Ellagitannin from Japanese Oak Sapwood," Org. Lett. 2014, 16, 1378–1381, DOI: 10.1021/ol500146a.


1: InChI=1S/C36H24O22/c37-11-2-8-15(24(44)20(11)40)16-9(3-12(38)21(41)25(16)45)36(53)56-29-14(5-54-32(8)49)55-33(50)10-4-13(39)22(42)26(46)19(10)30-17-6(34(51)57-30)1-7-18(23(17)43)31(58-35(7)52)28(48)27(29)47/h1-4,14,27-31,37-48H,5H2/t14-,27-,28-,29-,30-,31+/m1/s1

NMR Steven Bachrach 01 Apr 2014 No Comments

Computation-aided structure determination

I have not discussed any papers that utilize computations to confirm chemical structure in a while, so here are two recent examples.

Grabow has utilized MP2 and M06-2x computations to confirm the lowest energy conformation of (-)-lupinine 1.1 The interesting structural aspect of this compound is the possibility of an intramolecular hydrogen bond linking the hydroxyl group with the amine.


Using molecular mechanics, the authors identified 57 structures within 50 kJ mol-1 of each other. These geometries were reoptimized at MP2/6-311++G(d,p) and M06-2x/6-311++G(d,p).
The lowest energy structures had the expected trans ring fusion, with a trans relationship between the hydrogen on the bridgehead carbon (C9) and the hydroxymethyl group. This corresponds to either the (R,R) or (S,S) isomer. The three lowest energy structures are shown in Figure 1. Unfortunately, the geometry for the lowest energy isomer provided in the Supporting Materials is wrong, and the authors did not supply the geometries of the other isomers. This situation is unacceptable! Reviewers and editors must do a better job in policing the Supporting Materials; there is no excuse for not including all of the optimized structures, and better yet, in a more usable format that what has been done here. I have reoptimized these structures at M06-2x/6-31G(d). The lowest energy conformer 1a does possess the expected internal hydrogen bond.




Figure 1. M06-2x/6-31G(d) optimized structures of the three lowest energy conformers of 1, with relative free energies in kJ mol-1.

Table 1 provides a comparison of the MP2 computed values of important structural parameters along with the experimental values obtained from a microwave experiment. The agreement with the computed values for 1a provides strong evidence that this is the structure of (-)-lupinine.

Table 1. Comparison of MP2 and experimental structural parameters of 1.a


Expt. (1)

MP2 (1a)




























aRotational constants (A, B, C) in MHz, centrifugal distortion constants (ΔJ, ΔJK, ΔK) in kHz, and nuclear quadrupole coupling tensor elements (χaa, χbb, χcc) in MHz.

The second study utilizes computed NMR chemical shifts to discriminate potential diastereomeric structures. Laurefurenyne A was first assigned the structure 2 based on 1D and 2D NMR experiments. However, based on potential biochemical analogy to other compounds, Paton and Burton2 had doubts about this structure. In addition to synthesizing the natural material, they performed an extensive computational study of the chemical shifts of the diastereomers. For each of the 32 possible diastereomers, they performed a Monte Carlo search of the conformational space using molecular mechanics. The structures of all isomers within 10 kJ mol-1 of the lowest energy structure were reoptimized at ωB97X-D/6-31G(d) with PCM (CHCl3) and chemical shifts obtained at mPW1PW91/6-311G(d,p). Final chemical shifts were obtained using a Boltzmann weighting. The computed values for 2 were quite off from the experimental values, with a mean unsigned error of 1.5 ppm. A better assessment was provided with the DP4 method, which indicated that 3 has the highest probability of being the correct structure, a structure consistent with the likely biosynthetic pathway.




(1) Jahn, M. K.; Dewald, D.; Vallejo-López, M.; Cocinero, E. J.; Lesarri, A.; Grabow, J.-U. "Rotational Spectra of Bicyclic Decanes: The Trans Conformation of (-)-Lupinine," J. Phys. Chem. A 2013, DOI: 10.1021/jp407671m.

(2) Shepherd, D. J.; Broadwith, P. A.; Dyson, B. S.; Paton, R. S.; Burton, J. W. "Structure Reassignment of Laurefurenynes A and B by Computation and Total Synthesis," Chem. Eur. J. 2013, 19, 12644-12648, DOI: 10.1002/chem.201302349.


(-)-Lupinine 1: InChI=1S/C11H21NO/c1-11-6-2-3-7-12(11)8-4-5-10(11)9-13/h10,13H,2-9H2,1H3/t10-,11+/m0/s1

Laurefurenyne A 3: InChI=1S/C14H20O4.C2H6/c1-3-4-5-6-12-11(16)8-14(18-12)13-7-10(15)9(2)17-13;1-2/h1,4-5,9-16H,6-8H2,2H3;1-2H3/b5-4-;/t9-,10-,11-,12+,13-,14+;/m1./s1

NMR Steven Bachrach 09 Dec 2013 2 Comments

Aquatolide – structure revision brought on by computed NMR spectra

The natural product aquatolide has the proposed structure 1.1 Before starting to investigate this rather unusual structure – the 2[ladderane] component is rare and likely to be a synthetic challenge – Shaw and Tantillo opted to reassure themselves that the structure is correct.2 They computed the chemical shifts of this structure at mPW1PW91/6-311+G(2d,p)//B3LYP/6-31+G(d,p) including PCM to model chloroform. Surprisingly, the mean absolute deviation of the computed 13C NMR shifts of 1 with the experimental values is 7.23 ppm, with the largest deviation of 24.3 ppm. The largest deviation between 1 and the experimental 1H NMR shifts is 1.31 ppm. These large errors suggested that the structure is wrong. Surveying some 60 different possible alternative structures, largely based on other related compounds found in the same plant, they landed on 2. Here the mean absolute deviation of the computed 13C chemical shifts is only 1.37 ppm, with a maximum deviation of only 4.3 ppm. Similar dramatic improvement is also seen with the proton chemical shifts. Excellent agreement is also seen in the computed 1H-1H coupling constants between those computed for 2 and the experimental spectrum. Crystallization of aquatolide and subsequent determination of the structure using x-ray diffraction confirms that the actual structure of aquatolide is 2.




(1) San Feliciano, A.; Medarde, M.; Miguel del Corral, J. M.; Aramburu, A.; Gordaliza, M.; Barrero, A. F. "Aquatolide. A new type of humulane-related sesquiterpene lactone," Tetrahedron Lett. 1989, 30, 2851-2854, DOI: 10.1016/s0040-4039(00)99142-1

(2) Lodewyk, M. W.; Soldi, C.; Jones, P. B.; Olmstead, M. M.; Rita, J.; Shaw, J. T.; Tantillo, D. J. "The Correct Structure of Aquatolide—Experimental Validation of a Theoretically-Predicted Structural Revision," J. Am. Chem. Soc. 2012, DOI: 10.1021/ja3089394


1: InChI=1S/C15H18O3/c1-7-5-4-6-15-9(11(7)16)8-10(15)12(14(8,2)3)18-13(15)17/h5,8-10,12H,4,6H2,1-3H3/t8-,9+,10+,12+,15+/m1/s1

2: InChI=1S/C15H18O3/c1-7-5-4-6-15-9-8(10(7)16)11(15)14(2,3)12(9)18-13(15)17/h5,8-9,11-12H,4,6H2,1-3H3/b7-5-/t8-,9-,11+,12-,15+/m0/s1

NMR Steven Bachrach 05 Dec 2012 No Comments

Computed C-C NMR coupling constants

The use of computed NMR coupling constants is starting to grow. In a previous post I discussed a general study by Rablen and Bally on methods for computing JHH coupling constants. Now Williamson reports methods to experimentally obtain 1 JCC and 3JCC coupling constants.1 These were obtained for strychnine. He then computed the coupling constants in two steps. Using the B3LYP/6-31G(d) optimized geometry, first the Fermi contact contribution was computed at B3LYP/6-31+G(d,p) by uncontracting the basis set and adding an additional tighter set of polarization functions. Second, the remaining terms (spin-dipolar, paramagnetic spin-orbit and diamagnetic spin-orbit coupling) were computed with the 6-31+Gd,p) set without modifications. The two computed terms were added to give the final estimate.

A plot of the experimental vs. the DFT computed 1 JCC and 3JCC coupling constants shows
an excellent linear relation, with correlation coefficient of 0.9986 and a slope of 0.98. The mean absolute deviation for the computed and experimental 1 JCC and 3JCC coupling constants is 1.0
Hz and 0.4 Hz, respectively, both well within the experimental error.

I expect that computed NMR spectra will continue to be a growth area, especially for structural identification.


(1) Williamson, R. T.; Buevich, A. V.; Martin, G. E. "Experimental and Theoretical Investigation of 1JCC and nJCC Coupling Constants in Strychnine," Org. Letters 2012, 14, 5098-5101, DOI: 10.1021/ol302366s



NMR Steven Bachrach 14 Nov 2012 3 Comments

Structure of conicasterol F

Here is an interesting twist on using computations in conjunction with experimental NMR to solve for molecular structure. I have blogged a number of times on comparing computed chemical shifts with experimental values to identify structure, and also on using the comparison of computed and experimental coupling constants to accomplish this purpose.

Butts and Bifulco were interested in the structure of conicasterol F 1 and opted to make two sets of comparison.1 The first uses the traditional approach of comparing the computed and experimental 13C chemical shifts. The second comparison uses the distances between protons, coming from the optimized structure and the rotating-frame nuclear Overhauser effect (ROE).

Standard analysis of the NMR spectra of 1 allowed for the determination of all of the stereochemistry except for the epoxy ring at C8 and C14. The possible options are shown as 1a and 1b. The optimized geometries (MPW1PW91/6-31G) of these two diastereomers are shown in Figure 1.





Figure 1. Optimized geometries of 1a and 1b.

Comparison of 15 distances between protons determined by the ROE experiment and by computation led to a mean absolute error of 7.8% for 1a and 3.0% for 1b, suggesting that the latter is the correct structure. Similar comparison was then made between the experimental chemical shifts of 12 of the carbon atoms with the computed values of the two isomers. The mean absolute error in the chemical shifts of 1a is 3.7ppm, but only 0.8 ppm for 1b. Both methods give the same conclusion: conicasterol F has structure 1b.


(1) Chini, M. G.; Jones, C. R.; Zampella, A.; D’Auria, M. V.; Renga, B.; Fiorucci, S.; Butts, C. P.; Bifulco, G., "Quantitative NMR-Derived Interproton Distances Combined with Quantum Mechanical Calculations of 13C Chemical Shifts in the Stereochemical Determination of Conicasterol F, a Nuclear Receptor Ligand from Theonella swinhoei," J. Org. Chem., 2012, 77, 1489-1496, DOI: 10.1021/jo2023763.


1b: InChI=1/C29H46O4/c1-16(2)17(3)8-9-18(4)21-14-23(31)28-26(21,7)15-24-29(32-24)25(6)12-11-22(30)19(5)20(25)10-13-27(28,29)33-28/h16-18,20-24,30-31H,5,8-15H2,1-4,6-7H3/t17-,18-,20+,21-,22+,23+,24-,25+,26-,27+,28+,29+/m1/s1

NMR Steven Bachrach 01 May 2012 No Comments

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