Archive for the 'NMR' Category

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


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.

1

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

References

(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.

InChIs

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
InChIKey=PTEZCLBSJBUWFI-LJBUUXJGSA-N

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.


1

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.

1a
(0.0)

1b
(10.4)

12
(11.5)

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)

A

1414.126

1425.8

B

811.672

815.1

C

671.530

677.1

ΔJ

0.0255

0.023

ΔJK

0.0639

0.065

ΔK

0.0037

0.0022

χaa

1.9973

2.0

χbb

1.062

1.1

χcc

-3.059

-3.1

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.


2


3

References

(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.

InChIs

(-)-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
InChIKey=WVDUAOYJLFVEMW-WDEREUQCSA-N

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
InChIKey=ZYESDGGYHKCHMJ-SKFGUVSTSA-N

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


2

References

(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

InChIs

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
InChIKey=JGSDEQLPLHCECO-NIDGLEHPSA-N

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
InChIKey=OKZHLNWYFSWUMD-AETBLWMGSA-N

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.

References

(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

InChIs

strychnine:
InChI=1S/C21H22N2O2/c24-18-10-16-19-13-9-17-21(6-7-22(17)11-12(13)5-8-25-16)14-3-1-2-4-15(14)23(18)20(19)21/h1-5,13,16-17,19-20H,6-11H2/t13-,16-,17-,19-,20-,21+/m0/s1
InChIKey=QMGVPVSNSZLJIA-FVWCLLPLSA-N

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.


1a


1b

1a

1b

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.

References

(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.

InChIs

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
InChIKey=XTWHHLLDFQALAM-XAIGNWORBC

NMR Steven Bachrach 01 May 2012 No Comments

Welwitindolinones structure

A quick note here on the use of computed NMR to determine stereochemical structure. The Garg group synthesized two “oxidized welwitindolines”, compounds 1 and 2.1 The relative stereochemistry at the C3 position (the carbon with the hydroxy group) was unknown.


1


2

Low energy gas-phase conformers of both epimers of 1 and 2 were optimized at B3LYP/6-31+G(d,p). (These computations were done by the Tantillo group.) See Figure 1 for the optimized lowest energy conformers. Using these geometries the NMR chemical shifts were computed at mPW1PW91/6-311+G(d,p) with implicit solvent (chloroform). The chemical shifts were Boltzmann-weighted and scaled according to the prescription (see this post) of Jain, Bally and Rablen.2 The computed chemical shifts were then compared against the experimental NMR spectra. For both 1 and 2, the 13C NMR shifts could not readily distinguish the two epimers. However, the computed 1H chemical shifts for the S epimer of each compound was significantly in better agreement with the experimental values; the mean average deviation for the S epimer of 2 is 0.08 ppm but 0.36ppm for the R epimer. As a check of these results, DP4 analysis3 (see this post) of 2 indicated a 100% probability for the S epimer using only the proton chemical shifts or with the combination of proton and carbon data.

1

2

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

References

(1) Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.; Tantillo, D. J.; Garg, N. K., "Total Synthesis of Oxidized Welwitindolinones and (-)-N-Methylwelwitindolinone C Isonitrile," J. Am. Chem. Soc. 2011, 134, 1396-1399, DOI: 10.1021/ja210837b

(2) 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.

(3) 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

InChIs

1: InChI=1/C22H21ClN2O3S/c1-6-20(4)15(23)10-13-17(26)21(20,24-11-29)12-8-7-9-14-16(12)22(28,19(13,2)3)18(27)25(14)5/h6-10,13,28H,1H2,2-5H3/t13-,20+,21+,22-/m0/s1
InChIKey=VDNAFECSPBXWIH-WOHBTAIZBQ

2: InChI=1/C22H21ClN2O3/c1-7-20(4)15(23)11-13-17(26)21(20,24-5)12-9-8-10-14-16(12)22(28,19(13,2)3)18(27)25(14)6/h7-11,13,28H,1H2,2-4,6H3/t13-,20+,21+,22-/m0/s1
InChIKey=GFNPBZSGZFQTJA-WOHBTAIZBX

NMR Steven Bachrach 28 Feb 2012 1 Comment

Computed NMR of a large organometallic

Bergman and Raymond have prepared a Ga4L612- host that can encapsulate small monocations and neutral species.1,2 Figure 1 shows the host with an encapsulated tetraethylammonium ion NEt4+. (Note that the hydrogens have been suppressed for easier viewing. And be sure to click on the structure in order to interact with the 3-D model.)

Figure 1. Structure of the Ga4L612- host encapsulating NEt4+.

Of interest for readers of this blog is that they have now computed the NMR spectra of the encapsulated species.3 The geometry of the host is fixed to that found in the crystal structure where Cp*Co is the guest and the geometry of the guest (NEt4+, PEt4+ and others) is optimized with molecular mechanics. The complex is then computed at B3LYP with the 3-21G basis set for the host and the G-311(g,p) basis set for the guest. The computed 1H chemical shifts are actually within 0.1 ppm of experiment, and show the swapping of the relative position of the chemical shifts of the methyl vs methylene proton for the two guests.

This demonstrates the computed NMR shifts can be applied to some very large molecules including organometallics.

References

(1) Caulder, D. L.; Powers, R. E.; Parac, T. N.; Raymond, K. N., "The Self-Assembly of a Predesigned Tetrahedral M4L6 Supramolecular Cluster," Angew. Chem. Int. Ed. 1998, 37, 1840-1843, DOI: 10.1002/(SICI)1521-3773(19980803)37:13/14<1840::AID-ANIE1840>3.0.CO;2-D

(2) Biros, S. M.; Bergman, R. G.; Raymond, K. N., "The Hydrophobic Effect Drives the Recognition of Hydrocarbons by an Anionic Metal-Ligand Cluster," J. Am. Chem. Soc. 2007, 129, 12094-12095, DOI: 10.1021/ja075236i

(3) Mugridge, J. S.; Bergman, R. G.; Raymond, K. N., "1H NMR Chemical Shift Calculations as a Probe of Supramolecular Host-Guest Geometry," J. Am. Chem. Soc. 2011, 133, 11205-11212, DOI: http://dx.doi.org/10.1021/ja202254x

NMR Steven Bachrach 02 Feb 2012 No Comments

Calculating NMR proton-proton coupling constants

Bally and Rablen have followed up their important study of the appropriate basis sets and density functional needed to compute NMR chemical shifts1 (see this post) with this great examination of procedures for computing proton-proton coupling constants.2

They performed a comparison of 165 experimental coupling constants from 66 small, rigid molecules with computed proton-proton coupling constants. They use a variety of basis sets and functionals. They also test whether all four components that lead to nuclear-nuclear spin coupling constants are need, or if just the Fermi contact term would suffice.

The computationally most efficient procedure, one that still provides excellent agreement with the experimental coupling constants is the following:

  1. optimize the geometry at B3LYP/6-31G(d)
  2. Calculate only the proton-proton Fermi contact terms at B3LYP/6-31G(d,p)u+1s[H]. The basis set used for computing the Fermi contact terms is unusual. The basis set for hydrogen (denoted as “u+1s[H]”) uncontracts the core functions and adds one more very compact 1s function.
  3. Scale the Fermi contact terms by 0.9155 to obtain the proton-proton coupling constants.

This methodology provides coupling constants with a mean error of 0.51 Hz, and when applied to a probe set of 61 coupling constants in 37 different molecules (including a few that require a number of conformers and thus a Boltzmann-weighted averaging of the coupling constants) the mean error is only 0.56 Hz.

Bally and Rablen supply a set of scripts to automate the computation of the coupling constants according to this prescription; these scripts are available in the supporting materials and also on the Cheshire web site. It should also be noted that the procedure described above can be performed with Gaussian-09; no other software is needed. Thus, these computations are amenable to synthetic chemists with a basic understanding of quantum chemistry.

References

(1) 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.

(2) 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

NMR Steven Bachrach 13 Dec 2011 6 Comments

Computed NMR spectra predicts the structure of Nobilisitine A

Nobilisitine A was isolated by Evidente and coworkers, who proposed the structure 1.1 Banwell and co-workers then synthesized the enantiomer of 1, but its NMR did not correspond to that of reported for Nobilisitine A.; the largest differences are 4.7 ppm for the 13C NMR and 0.79 ppm for the 1H NMR.2


1

Lodewyk and Tantillo3 examined seven diastereomers of 1, all of which have a cis fusion between the saturated 5 and six-member rings (rings C and D). Low energy conformations were computed for each of these diasteromers at B3LYP/6-31+G(d,p). NMR shielding constants were then computed in solvent (using a continuum approach) at mPW1PW91/6-311+G(2d,p). A Boltzmann weighting of the shielding contants was then computed, and these shifts were then scaled as described by Jain, Bally and Rablen4 (discussed in this post). The computed NMR shifts for 1 were compared with the experimental values, and the mean deviations for the 13C and 1H svalues is 1.2 and 0.13 ppm, respectively. (The largest outlier is 3.4 ppm for 13C and 0.31 for 1H shifts.) Comparison was then made between the computed shifts of the seven diasteomers and the reported spectrum of Nobilisitine A, and the lowest mean deviations (1.4 ppm for 13C and 0.21 ppm for 1H) is for structure 2. However, the agreement is not substantially better than for a couple of the other diasteomers.


2

They next employed the DP4 analysis developed by Smith and Goodman5 for just such a situation – where you have an experimental spectrum and a number of potential diastereomeric structures. (See this post for a discussion of the DP4 method.)The DP4 analysis suggests that 2 is the correct structure with a probability of 99.8%.

Banwell has now synthesized the compound with structure 2 and its NMR matches that of the original natural product.6 Thus Nobilisitine A has the structure 2.

References

(1) Evidente, A.; Abou-Donia, A. H.; Darwish, F. A.; Amer, M. E.; Kassem, F. F.; Hammoda, H. A. m.; Motta, A., "Nobilisitine A and B, two masanane-type alkaloids from Clivia nobilis," Phytochemistry, 1999, 51, 1151-1155, DOI: 10.1016/S0031-9422(98)00714-6.

(2) Schwartz, B. D.; Jones, M. T.; Banwell, M. G.; Cade, I. A., "Synthesis of the Enantiomer of the Structure Assigned to the Natural Product Nobilisitine A," Org. Lett., 2010, 12, 5210-5213, DOI: 10.1021/ol102249q

(3) Lodewyk, M. W.; Tantillo, D. J., "Prediction of the Structure of Nobilisitine A Using Computed NMR Chemical Shifts," J. Nat. Prod., 2011, 74, 1339-1343, DOI: 10.1021/np2000446

(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, DOI: 10.1021/jo900482q.

(5) 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

(6) Schwartz, B. D.; White, L. V.; Banwell, M. G.; Willis, A. C., "Structure of the Lycorinine Alkaloid Nobilisitine A," J. Org. Chem., 2011, ASAP, DOI: 10.1021/jo2016899

InChIs

2: InChI=1/C17H19NO4/c19-12-3-8-1-2-18-17(8)16-10-6-15-14(21-7-22-15)5-9(10)13(20)4-11(12)16/h5-6,8,11-12,16-19H,1-4,7H2/t8-,11-,12-,16-,17-/m0/s1

InChIKey=JISHLXUXALHAET-PUYTVRRYBF

NMR Steven Bachrach 15 Nov 2011 3 Comments

cyclopenta[b]benzofuran – stereochemistry and mechanism of formation

Here is a nice example of an interesting synthesis, mechanistic explication using computation (with a bit of an unanswered question), and corroboration of the stereochemistry of the product using computed NMR shifts. Gil and Mischne1 reacted dimedone 1 with dienal 2 under Knoevenagel conditions to give, presumably, 3. But 3 is not recovered, rather the tricycle 4 is observed.

There are four stereoisomers that can be made (4a-d). Computed 13C chemical shifts at OPBE/pcS-1 (this is a basis set suggested for computing chemical shifts2) for these four isomers were then compared with the experimental values. The smallest root mean squared error is found for 4d. Better still, is that these authors utilized the DP4 method of Goodman3 (see this post), which finds that 4d agrees with the experiment with 100% probability!

Lastly, the mechanism for the conversion of 3 to 4 was examined at M06/6-31+G**. The optimized geometries of the starting material, transition state, and product are shown in Figure 1. The free energy barrier is a modest 14.5 kcal mol-1. The TS indicates a conrotatory 4πe- electrocyclization. The formation of the C-O bond lags far behind in the TS. They could not identify a second transition state. It would probably be worth examining whether the product of this 4πe- electrocyclization could be located, perhaps with an IRC starting from the transition state. Does this TS really connect 3 to 4?

3

TS

4

Figure 1. M06/6-31+G** optimized geometries of 3 and 4 and the transition state connecting them.

References

(1) Riveira, M. J.; Gayathri, C.; Navarro-Vazquez, A.; Tsarevsky, N. V.; Gil, R. R.; Mischne, M. P., "Unprecedented stereoselective synthesis of cyclopenta[b]benzofuran derivatives and their characterisation assisted by aligned media NMR and 13C chemical shift ab initio predictions," Org. Biomol. Chem., 2011, 9, 3170-3175, DOI: 10.1039/C1OB05109A

(2) 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

(3) 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

InChIs

1: InChI=1/C8H12O2/c1-8(2)4-6(9)3-7(10)5-8/h3-5H2,1-2H3
InChIKey=BADXJIPKFRBFOT-UHFFFAOYAX

2: InChI=1/C12H12O/c1-11(10-13)6-5-9-12-7-3-2-4-8-12/h2-10H,1H3/b9-5+,11-6+
InChIKey=VFBDYWDOVMUDEB-MPEOSAONBY

3: InChI=1/C20H22O2/c1-15(8-7-11-16-9-5-4-6-10-16)12-17-18(21)13-20(2,3)14-19(17)22/h4-12H,13-14H2,1-3H3/b11-7+,15-8+
InChIKey=IBEGRISKTNRVOU-YQQAFNMCBC

4d: InChI=1/C20H22O2/c1-19(2)11-15(21)17-16(12-19)22-20(3)10-9-14(18(17)20)13-7-5-4-6-8-13/h4-10,14,18H,11-12H2,1-3H3/t14-,18+,20+/m1/s1
InChIKey=VEGSTZFBNRXEAX-WNYOCNMUBZ

electrocyclization &NMR Steven Bachrach 23 Aug 2011 3 Comments

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