Archive for the 'Optical Rotation' Category

Computing OR: norbornenone

Optical activity is a major tool for identifying enantiomers. With recent developments in computational techniques, it is hoped that experiments combined with computations will be a powerful tool for determining absolute configuration. The recent work of Lahiri, et al. demonstrates the scope of theoretical work that is still needed to really make this approach broadly applicable.1

They prepared (1R,4R)-norbornenone 1 and measured its optical rotation in the gas phase and in dilute solutions of acetonitrile and cyclohexane. The specific rotations at three different wavelengths are listed in Table 1. Of first note is that though there is some small differences in solution, as expected, there really is substantial differences between the gas- and solution phases. Thus cautionary point 1: be very careful of comparing solution phase experimental optical activity with computed gas phase predictions.


1

Table 1. Experimental and computed specific rotation of 1.

 

355.0 nm

589.3 nm

633.0 nm

Gas phase

Expt

6310

755

617

B3LYP

10887

1159

944

CCSD

3716

550

453

Acetonitrile solution

Expt

8607

950

776

PCM/B3LYP

11742

1277

1040

Cyclohexane solution

Expt

9159

981

799

PCM/B3LYP

11953

1311

1069

For the computations, the geometry of 1 was optimized at B3LYP/aug-cc-pVTZ (see Figure 1. The OR was computed at B3LYP with different basis sets, finding that the difference in the predicted specific rotation at 598.3nm differs only quite little (90.6 deg dm-1 (g/mL)-1) between the computations using aug-cc-pVTZ and aug-cc-pVQZ) suggesting that the basis set limit has been reached. The gas –phase computed values at B3LYP and CCSD are also shown in Table 1. Though these computations do get the correct sign of the rotation, they are appreciably off of the experimental values, and the percent error varies with wavelength. Cautionary point 2: it is not obvious what is the appropriate computational method to compute OR, and beware of values that seem reasonable at one wavelength – this does not predict a good agreement at a different wavelength.

Figure 1. Optimized geometry of 1 at B3LYP/aug-cc-pVTZ.

Lastly, computed solution values of the OR were performed with PCM and B3LYP. These values are given in Table 1. Again the agreement is poor. So cautionary point 3: computed (PCM) solution OR
may be in quite poor agreement with experiment.

Often the culprit to poor agreement between computed and experimental OR is attributed to omitted vibrational effects, but in this case, because 1 is so rigid, one might not expect too much error to be caused by the effects of vibrations. So the overall result – we need considerable work towards addressing how to accurately compute optical activity!

References

(1) Lahiri, P.; Wiberg, K. B.; Vaccaro, P. H.; Caricato, M.; Crawford, T. D. "Large Solvation Effect in the Optical Rotatory Dispersion of Norbornenone," Angew. Chem. Int. Ed. 2014, 53, 1386-1389, DOI: 10.1002/anie.201306339.

InChIs

1: InChI=1S/C7H8O/c8-7-4-5-1-2-6(7)3-5/h1-2,5-6H,3-4H2/t5-,6+/m1/s1
InChIKey=HUQXEIFQYCVOPD-RITPCOANSA-N

DFT &Optical Rotation Steven Bachrach 25 Feb 2014 2 Comments

ORD of methyloxirane

Computing the optical rotation of simple organic molecules can be a real challenge. One of the classic problems is methyloxirane. DFT typically gets the wrong sign, let alone the wrong value. Cappelli and Barone1 have developed a QM/MM procedure where methyloxirane is treated with DFT (B3LYP/aug-cc-pVDZ or CAM-B3LYP/aubg-cc-pVDZ). Then 2000 arrangements of water about methyloxirane were obtained from an MD simulation. For each of these configurations, a supermolecule containing methyloxirane and all water molecules with 16 Å was identified. The waters of the supermolecule were treated as a polarized force field. This supermolecule is embedded into bulk water employing a conductor-polarizable continuum model (C-PCM). Lastly, inclusion of vibrational effects, and averaging over the 2000 configurations, gives a predicted optical rotation at 589 nm that is of the correct sign (which is not accomplished with a gas phase or simple PCM computation) and is within 10% of the correct value. The full experimental ORD spectrum is also quite nicely matched using this theoretical approach.

References

(1) Lipparini, F.; Egidi, F.; Cappelli, C.; Barone, V. "The Optical Rotation of Methyloxirane in Aqueous Solution: A Never Ending Story?," J. Chem. Theor. Comput. 2013, 9, 1880-1884, DOI: 10.1021/ct400061z.

InChIs

(R)-Methyloxirane:
InChI=1S/C3H6O/c1-3-2-4-3/h3H,2H2,1H3/t3-/m1/s1
InChIKey=GOOHAUXETOMSMM-GSVOUGTGSA-N

DFT &Optical Rotation Steven Bachrach 15 May 2013 2 Comments

Basis sets for OR

What is the appropriate basis set to use for computing optical rotations? Hedgård, Jensen, and Kongsted examined the optical rotation of 1-6 using B3LYP and CAM-B3LYP at two different wavelengths.1 They examined a series of different basis sets, including the aug-pCS sets2 (developed for NMR computations), the aug-cc-pVXZ series and 6-311++G(3df,3pd). They compared the computed optical rotation with the different basis sets with the value obtained from an extrapolated basis set computation. The mean absolute deviation using either B3LYP or CAM-B3LYP at the two different basis sets are listed in Table 1. The bottom line is that aug-pcS-2 is the preferred method, but this basis set is rather large and computations of big molecules will be difficult. The aug-pcS-1 set is the best choice for large molecules. Errors with the extensive Pople basis set and the aug-cc-pVXZ sets are quite sizable and of concern (especially at the shorter wavelength). It should also be mentioned that even with the largest aug-pcS basis sets extrapolated to the CBS limit, the computed value of the optical rotation of 3 has the wrong sign! Clearly, basis set choice is not the only issue of concern. We remain in need of a robust methodology for computing optical activity.

Table 1. Mean absolute deviation of the optical activities of 1-6 evaluated at two wavelengths.

 

589.3 nm

355.0 nm

Basis set

B3LYP

CAM-B3LYP

B3LYP

CAM-B3LYP

aug-pcS-1

4.5

2.2

20.8

15.3

aug-pcS-2

1.4

1.1

4.0

1.5

aug-cc-pVDZ

15.6

13.6

62.2

144.1

aug-cc-pVTZ

3.9

6.3

9.2

37.0

6-311++G(3df,3pd)

6.4

10.3

20.5

40.7

References

(1) Hedegård, E. D.; Jensen, F.; Kongsted, J. "Basis Set Recommendations for DFT Calculations of Gas-Phase Optical Rotation at Different Wavelengths," J. Chem. Theory Comput. 2012, 8, 4425-4433, DOI: 10.1021/ct300359s

(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

Optical Rotation Steven Bachrach 11 Dec 2012 2 Comments

Regiolone and isosclerone: enantiomers resolved

It is striking to me that the absolute configuration of relatively simple compounds remains problematic even today. The structure of two naturally-occurring phytotoxic enantiomers 1, called regiolone and isosclerone, are finally definitively defined using a computational approach.


(R)-1: R = OH, R’ = H
(S)-1: R = H, R’ = OH

Isosclerone is the dextrorotatory isomer, while regiolone is the levorotatory isomer. The question though is which one is R and which one is S? Evidente and co-workers arbitrarily decided to compute the spectral properties of the S isomer.1 They located four low energy conformers at B3LYP/6-31G* and B3LYP/TZVP. (These conformers are not shown here as the authors did not deposit the coordinates. Reviewers and editors – please insist that this computational data be mandatory for publication!) The conformer relative energies, listed in Table 1, are dependent on the method, however, the two lowest energy structures will dominate the population and both will be present to a significant extent, regardless of which energy set is used. The optical rotation [α]D was computed at B3LYP/6-31G*//B3LYP/TZVP, and these too are listed in Table 1. The Boltzmann-weighted [α]D is 21.8. Even though the lowest energy conformer contributes a negative rotation, the much larger positive rotation due to the second-lowest energy conformer, along with the two other conformers, will dominate to dictate the OR value. This suggests that the enantiomers are (S)(+)-1 and (R)(-)-1. Computed ECD spectra confirm this assignment; the computed ECD of the (S) isomer is a near mirror image of the experimental ECD of the (-)-1 compound. Therefore, regiolone is (R)(-)-1 and isosclerone is (S)(+)-1.

Table 1. Relative free energies (kcal mol-1) and [α]D of the conformers of (S)-1.a

conformer

ΔG, 6-31G*

ΔG, TZVP

[α]Db

A 0.43 0.0 -17.50
B 0.0 0.32 67.92
C 1.21 1.03 95.72
D 1.84 1.48 17.72

aAll computations performed with B3LYP. bAt B3LYP/6-31G*//B3LYP/TZVP

References

(1) Evidente, A.; Superchi, S.; Cimmino, A.; Mazzeo, G.; Mugnai, L.; Rubiales, D.; Andolfi, A.; Villegas-Fernández, A. M., "Regiolone and Isosclerone, Two Enantiomeric Phytotoxic Naphthalenone Pentaketides: Computational Assignment of Absolute Configuration and Its Relationship with Phytotoxic Activity," Eur. J. Org. Chem., 2011, 5564-5570, DOI: 10.1002/ejoc.201100941

InChIs

Regiolone: InChI=1/C10H10O3/c11-7-4-5-9(13)10-6(7)2-1-3-8(10)12/h1-3,7,11-12H,4-5H2/t7-/m1/s1
InChIKey=ZXYYTDCENDYKBR-SSDOTTSWBB

Isosclerone: InChI=1/C10H10O3/c11-7-4-5-9(13)10-6(7)2-1-3-8(10)12/h1-3,7,11-12H,4-5H2/t7-/m0/s1
InChIKey=ZXYYTDCENDYKBR-ZETCQYMHBD

Optical Rotation Steven Bachrach 13 Mar 2012 2 Comments

Palau’amine structure

Palau’amine has been of interest since its discovery in the early 1990s. It was just recently synthesized by Baran,1 to much acclaim. The structure of palau’amine underwent numerous revisions, and though the relative configuration had been settled, the absolute configuration was only determined by Reinscheid and Griesinger using a combination of experimental and computed ECD and ORD spectra.2


1

3,4-dibromopalau’amine 1 was subjected to careful NMR analysis to set as much of the overall structure as possible. Then two conformations were optimized at B3LYP/6-31G(d), one of which is displayed in Figure 1.

1

Figure 1. B3LYP/6-31G(d) optimized structure of 1.

TD-DFT computations including PCM gave an ECD spectrum that nicely matches with experiment, especially where the positive and negative peaks occur. The computed and experimental ORD spectra also match well, with all the signs matching up and a difference in the absolute value of the rotation of no more that 25%. The resulting absolute configuration is (-)-(6S,10R,11S,12S,16R,17S,18S,20S)-dibromopalau’amine, demonstrating again the power of combining computation and experiment for structure determination!

References

(1) Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J.; Baran, P. S., "Total Synthesis of Palau’amine," Angew. Chem. Int. Ed., 2010, 49, 1095-1098, DOI: 10.1002/anie.200907112

(2) Reinscheid, U. M.; Köck, M.; Cychon, C.; Schmidts, V.; Thiele, C. M.; Griesinger, C., "The Absolute Configuration of Dibromopalau’amine," Eur. J. Org. Chem., 2010, 6900-6903, DOI: 10.1002/ejoc.201001392

InChI

1: InChI=1/C17H22Br2ClN9O2/c18-6-1-7-11(30)28-3-5-4(2-21)9(20)16(13(31)25-15(23)26-16)8(5)17(28)12(24-14(22)27-17)29(7)10(6)19/h1,4-5,8-9,12-13,24-27,31H,2-3,21-23H2/q+2/p+1/t4-,5-,8+,9+,12+,13+,16+,17-/m1/s1/fC17H23Br2ClN9O2/h21H/q+3
InChIKey=VGQTUXLYZXIYTJ-CAGSSHLPDN

Optical Rotation Steven Bachrach 28 Mar 2011 1 Comment

Computed ECD of a coumarin with axial chirality

It’s been a while since I blogged about the use of computed spectra to determine the structure or configuration of a compound. Well, here’s a nice example of the use of computed electronic circular dichroism to determine the configuration of a coumarin that displays axial chirality.

Mazzanti and coworkers have synthesized a series of coumarins,1 obtained their ECD and computed their structures, stero-interconversion barriers (at B3LYP/6-31G(d)) and ECD (at TD-DFT/B3LYP/6-311++G(2d,p)//B3LYP/6-31G(d)). I will mention explicitly here just one example, compound 1, which elutes off a chiral column in two mirror image forms, both of which do not stereomutate over time.


1

The computed structure of 1 is shown in Figure 1 and the barrier for steromutation is predicted to be quite large, 35.7 kcal mol-1. This explains the lack of stereomutation. The computed ECD of 1M matches very well with the experimental ECD of the first eluted isomer, making the second eluted isomer 1P.

1

Figure 1. B3LYP/6-31G(d) optimized structure of 1.

References

(1) Lunazzi, L.; Mancinelli, M.; Mazzanti, A.; Pierini, M., "Stereomutation of Axially Chiral Aryl Coumarins," J. Org. Chem., 2010, ASAP, DOI: 10.1021/jo101261k

InChIs

1 (6-isopropyl-4-(2-methyl-1-naphthyl)chromen-2-one):
InChI=1/C23H20O2/c1-14(2)17-10-11-21-19(12-17)20(13-22(24)25-21)23-15(3)8-9-16-6-4-5-7-18(16)23/h4-14H,1-3H3
InChIKey=OEQFRNPVUJVJFO-UHFFFAOYAS

Optical Rotation Steven Bachrach 15 Sep 2010 1 Comment

Optical activity of a chiral calix[4]arene

Determination of absolute configuration remains a difficult undertaking, one usually solved by x-ray crystallography. In my book (Chapter 1.6.3) and blog (see these posts) I have noted the use of computations in conjunction with optical rotation or electronic circular dichroism as an alternative: possible configurations are optimized and their optical properties are computed and then matched against experimental spectra.

Neri and coworkers have utilized this approach to determine the absolute configuration of the chiral calix[4]arene 1.1

Computed optical rotations (TDDFT/B3LYP/6-31G* at 5 frequencies) are compared with experimental values in Table 1. While the magnitude is off (as is typical) the sign of the activity along with the trend matches up very well for the cS configuration shown in Figure 1. It should be noted that a second conformation makes up about 10% of the Boltzmann population, and the contribution of this second configuration is included in the computed values shown in Table 1. In addition, computations at higher levels give very similar results. Lastly, the computed ECD spectrum of the cS isomer also matches up well with experiment.

Table 1. Optical rotation of the cS isomer of 1 compared with experiment

Wavelength (nm)

Experiment

Computed

589.3

108

58.8

577

120

61.7

546

140

70.2

435

264

122.6

405

367

147.6

Figure 1. B3LYP/6-31G* optimized structure of the major conformation of 1.

Given the relatively low level of theory employed here, further use of this combined experimental/computational approach to obtaining absolute configurations of large molecules is encouraged.

References

(1) Talotta, C.; Gaeta, C.; Troisi, F.; Monaco, G.; Zanasi, R.; Mazzeo, G.; Rosini, C.; Neri, P., "Absolute Configuration Assignment of Inherently Chiral Calix[4]arenes using DFT Calculations of Chiroptical Properties," Org. Lett., 2010, 12, 2912-2915, DOI: 10.1021/ol101098x

InChIs

1: InChI=1/C59H78O7/c1-16-19-64-53-36-22-35-32-47(59(13,14)15)50(51-48(61)33-45(60)34-49(51)62)46(52(35)63)31-41-30-44(58(10,11)12)29-40(55(41)66-21-18-3)24-39-28-43(57(7,8)9)27-38(54(39)65-20-17-2)23-37(53)26-42(25-36)56(4,5)6/h25-30,32-34,60-63H,16-24,31H2,1-15H3
InChIKey=VGWOVZXMYMCPQO-UHFFFAOYAS

calixarenes &Optical Rotation Steven Bachrach 01 Sep 2010 No Comments

Fantastic optical activity of an octaphyrin

The octaphyrin 1 has been prepared and its crystal structure and electronic circular dichroism (ECD) spectra reported.1 The x-ray structure identified the compound as having the M,M helical structure. The optical rotation however could not be determined.


1

Rzepa now reports the computed ECD spectrum and optical activity of 1 and some related compounds.2 These computed spectra were obtained using TD0DFT with the B3LYP/6-31G(d) method with the CPCM treatment of the dichloromethane solvent. (The structure of 1 and other computed properties are available from the enhanced web table that Rzepa has deposited with the article (here). Once again this material seems to be available only to subscribers! My repeated discussions with ACS Pubs people that these “web objects” should be treated as data and not as copyrighted materials have fallen on deaf ears.) The computed ECD spectrum matches nicely with the experimental one, except that the signs at 570 and 620 nm are opposite. Rzepa suggests that either the compound is really of P,P configuration or the authors of experimental work have erroneously switched their assignments.

The computed value of [α]D of 1 is about -4000 °, with the negative sign in agreement with the sign for [α]D of M-hexahelicene. However, what is truly fantastic is the magnitude of the optical activity of the dication of 1 produced by loss of 2 electrons. This dication should be aromatic and it is predicted to have [α]1000 = -31597°!

References

(1) Werner, A.; Michels, M.; Zander, L.; Lex, J.; Vogel, E., ""Figure Eight" Cyclooctapyrroles: Enantiomeric Separation and Determination of the Absolute Configuration of a Binuclear Metal Complex," Angew. Chem. Int. Ed. 1999, 38, 3650-3653, DOI: 10.1002/(SICI)1521-3773(19991216)38:24<3650::AID-ANIE3650>3.0.CO;2-F

(2) Rzepa, H. S., "The Chiro-optical Properties of a Lemniscular Octaphyrin," Org. Lett. 2009, 11, 3088–3091DOI: 10.1021/ol901172g

Aromaticity &Optical Rotation Steven Bachrach 01 Sep 2009 2 Comments

CD of high-symmetry molecules

I have written a number of blog posts that deal with the computation of optical activity. Trindle and Altun have now reported TD-DFT computations of circular dichroism of high-symmetry molecules.1 The employ either B3LYP (with a variety of basis sets, the largest being 6-311++G(2d,2p)) and SOAP/ATZP. For a number of the high symmetry molecules (two examples are shown in Figure 1), the two methods differ a bit in their predictions of the first excited state, with SOAP typically predicting a red shift relative to the B3LYP. However, both methods general give the same sign of the CD signals and their line shapes are similar.


1


2

Figure 1. B3LYP/6-31G(d) optimized structures of 1 and 2 (again due to incomplete supporting materials, I reoptimized these structures)

References

(1) Trindle, C.; Altun, Z., "Circular dichroism of some high-symmetry chiral molecules: B3LYP and SAOP calculations " Theor. Chem. Acc. 2009, 122, 145-155, DOI: 10.1007/s00214-008-0494-8.

InChIs

1: InChI=1/C18H14O2/c19-15-7-11-3-1-4-12-8-16(20)10-14-6-2-5-13(9-15)18(14)17(11)12/h1-6H,7-10H2
InChIKey=DYZSIUYFWKNLHS-UHFFFAOYAB

2: InChI=1/C20H24/c1-13-9-18-7-8-20-12-15(3)19(11-16(20)4)6-5-17(13)10-14(18)2/h9-12H,5-8H2,1-4H3
InChIKey=JTMLLDPOLFRPGJ-UHFFFAOYAC

DFT &Optical Rotation Steven Bachrach 27 Jul 2009 No Comments

Optical activity of a [3,3]paracyclophane

Computed optical activity was utilized in establishing the absolute configuration of the [3,3]paracyclophane 1.1 The helical twist of this molecule makes it chiral.


1

The specific rotation of (-)-1 was measured to be -123 ° [dm (g/cm3) -1]. Seven different conformations of R-1 were optimized, having either D2, C2, or C1 symmetry, at B3LYP/TZVP. The two lowest energy conformers (at B3LYP/6-31G(d) – the authors did not supply coordinates in their supporting materials!) are shown in Figure 1.

1a (0.0)

1b (0.49)

Figure 1. B3LYP/6-31G(d) optimized structures and relative energy (kcal mol-1 of the two lowest energy conformers of 1.

The TDDFT computed value for [α]D for the lowest energy conformer is -171.7 ° [dm (g/cm3)-1]. In fact, the range of [α]D for seven conformers is -124.4 to -221.8. These values are consistent with the experimental observation in both sign and magnitude. The computed CD spectrum of the seven R-1 conformations are similar to the experimental spectra of (-)-1. Thus, one can conclude that the two enantiomers are R-(-)-1 and S-(+)-1.

References

(1) Muranaka, A.; Shibahara, M.; Watanabe, M.; Matsumoto, T.; Shinmyozu, T.; Kobayashi, N., "Optical Resolution, Absolute Configuration, and Chiroptical Properties of Three-Layered [3.3]Paracyclophane(1)," J. Org. Chem., 2008, 73, 9125-9128, DOI: 10.1021/jo801441h

InChIs

1: InChI=1/C31H38/c1-3-7-28-22-30-12-6-10-27-20-18-26(19-21-27)9-5-11-29(28)23-31(30)13-4-8-25-16-14-24(2)15-17-25/h14-23H,3-13H2,1-2H3
InChIKey=GFTKQZANYFICNS-UHFFFAOYAN

DFT &Optical Rotation Steven Bachrach 05 Jan 2009 No Comments

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