Wednesday, January 10, 2018

Antiaromatic compounds stabilized by benzenoid fusion

Konishi, A.; Okada, Y.; Nakano, M.; Sugisaki, K.; Sato, K.; Takui, T.; Yasuda, M., "Synthesis and Characterization of Dibenzo[a,f]pentalene: Harmonization of the Antiaromatic and Singlet Biradical Character." J. Am. Chem. Soc. 2017, 139, 15284
Jin, Z.; Teo, Y. C.; Teat, S. J.; Xia, Y., "Regioselective Synthesis of [3]Naphthylenes and Tuning of Their Antiaromaticity." J. Am. Chem. Soc. 2017, 139, 15933
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

Antiaromatic compounds by definition are unstable and so difficult to prepare. One approach to increase their stability is to fuse aromatic ring(s) onto the antiaromatic system. I discuss in this blog post two different scaffolds where this approach has been successful in preparing molecules that express some degree of antiaromaticity. In addition, I mention a technique to aid in evaluating the aromatic/antiaromatic character.

Pentalene 1 is a formal 8-π electron system and would be antiaromatic. To avoid this antiaromatic character, the double bonds are localized. Fusing benzenoid rings to pentalene to give dibenzo[a,e]penatalene 2 has been done, but the central rings avoid antiaromatic character by expressing the Kekule structure shown below.
Yasuda and coworkers report the preparation of mesityl-substituted dibenzo[a,f]penatalene
3.1 Resonance structures of 3¸ shown below, either have only one aromatic ring, or have two aromatic rings along with a trimethylenemethane (TMM) diradical component. Thus, one might expect 3 to express more antiaromatic character than 2.
NICS(1) values, computed at B3LYP/6-31G**, for 2 are -6.23 for the 6-member ring and +5.87 ppm for the 5-member ring, showing reduced aromaticity of the former ring. In sharp contrast, the NICS(1) values for 3 are +7.48 for the 6-member ring and +25.5 ppm for the 5-member ring, indicating substantial antiaromatic character for both rings. The calculated spin density distribution shows largest unpaired density on the expected carbon atoms based on the resonance structures involving the TMM fragment.

Xia and coworkers have prepared substituted analogues of the three structural isomers whereby three naphthylene units are fused together creating two cyclobutadienoid rings.2 These three frameworks are molecules 4-6. The 4-member rings are formally antiaromatic, tempered by the fused aromatic naphthylene groups. The question is then how does the different attachment geometry manifest in aromatic and/or antiaromatic character?
The computations take advantage of the NICS-XY method – well, a variation of this method. I had meant to write a post about the NICS-XY method when Stanger published it,3 but I just never got around to it. The idea is that NICS is evaluated typically at a single point, and just which point to use has been the subject of some discussion. Instead, Stanger proposes the NICS-XY method as a grid of points perpendicular to the plane of the molecule, typically in the plane bisecting the molecule. Trends in the values as one moves across the ring and perpendicular to the ring could assist in identifying aromatic/antiaromatic behaviour.

Xia computed the NICSπZZ along a line in the molecular plane bisecting the rings. This is shown in the figure below, which I have reproduced from the article. For example, for 4, which is compound 1 in the Xia paper and the figure below, the NICS values are taken along the line that horizontally bisects the molecule. In ring A, the values are negative, indicative of an aromatic ring. Across ring B, the values are still negative, but not as negative as for ring A, indicating a diminished aromaticity. In ring C, the values are positive, as one would expect for the antiaromatic cyclobutadienoid ring.

Figure taken from J. Am. Chem. Soc. 2017139, 15933-15939.

The authors highlight two trends. First, in the linear fusion (see the inset above), the aromatic ring fused to the cyclobutadienoid ring expresses diminished aromaticity. This can be understood in the following way. In naphthalene, the C2-C3 bond is longer than the C1-C2 bond. When the cyclobutadienoid is fused at the C2-C3 bond, it can lengthen even more to weaken the antiaaromaticity of the 4-member ring, and this consequently reduces the aromaticity of the 6-member ring. Fusion of the cyclobutadienoid ring at C1-C2, the shorter bond, causes a higher degree of antiaromaticity in the 4-member ring. The lengthening of this C1-C2 bond to try to reduce the antiromaticity of the 4-member ring leads to greater bond equalization in the 6-member ring, and its consequently greater aromatic character.


References

1. Konishi, A.; Okada, Y.; Nakano, M.; Sugisaki, K.; Sato, K.; Takui, T.; Yasuda, M., "Synthesis and Characterization of Dibenzo[a,f]pentalene: Harmonization of the Antiaromatic and Singlet Biradical Character." J. Am. Chem. Soc. 2017139, 15284-15287, DOI: 10.1021/jacs.7b05709.
2. Jin, Z.; Teo, Y. C.; Teat, S. J.; Xia, Y., "Regioselective Synthesis of [3]Naphthylenes and Tuning of Their Antiaromaticity." J. Am. Chem. Soc. 2017139, 15933-15939, DOI: 10.1021/jacs.7b09222.
3. Gershoni-Poranne, R.; Stanger, A., "The NICS-XY-Scan: Identification of Local and Global Ring Currents in Multi-Ring Systems." Chem. Eur. J. 201420, 5673-5688, DOI: 10.1002/chem.201304307.


InChIs

1: InChI=1S/C8H6/c1-3-7-5-2-6-8(7)4-1/h1-6H
InChIKey=GUVXZFRDPCKWEM-UHFFFAOYSA-N
2: InChI=1S/C16H10/c1-3-7-13-11(5-1)9-15-14-8-4-2-6-12(14)10-16(13)15/h1-10H
InChIKey=OZEPXROCWSMGGM-UHFFFAOYSA-N
3: InChI=1S/C16H10/c1-3-7-14-11(5-1)9-13-10-12-6-2-4-8-15(12)16(13)14/h1-10H
InChIKey=XOERMEAUYMRNNZ-UHFFFAOYSA-N
4: InChI=1S/C30H16/c1-2-6-18-10-24-23(9-17(18)5-1)27-13-21-15-29-25-11-19-7-3-4-8-20(19)12-26(25)30(29)16-22(21)14-28(24)27/h1-16H
InChIKey=CHDMCKMZQIHGAH-UHFFFAOYSA-N
5: InChI=1S/C30H16/c1-3-7-19-15-27-25(13-17(19)5-1)23-11-9-22-21(29(23)27)10-12-24-26-14-18-6-2-4-8-20(18)16-28(26)30(22)24/h1-16H
InChIKey=LPXGODOTGXTPRU-UHFFFAOYSA-N
6: InChI=1S/C30H16/c1-2-7-19-13-26-25(12-18(19)6-1)27-15-21-9-10-22-24-11-17-5-3-4-8-20(17)14-29(24)30(22)23(21)16-28(26)27/h1-16H
InChIKey=BKMGPFRQJXDFJQ-UHFFFAOYSA-N

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Tuesday, December 26, 2017

Efficient prediction of reaction paths through molecular graph and reaction network analysis

Yeonjoon Kim, Jin Woo Kim, Zeehyo Kim and Woo Youn Kim (2017)
Highlighted by Jan Jensen

Figure 2 from the paper. Reproduced under the CC-BY licence.

The paper presents an interesting approach to generating the most important intermediates given reactants and products. 

1. The reactants and products are mapped to atom connectivity (AC) matrices, where the presence and absence of bonds are represented by 1's and 0's. 

2. Intermediates are then enumerated by changing the matrix elements using simple rules and constraints are employed to keep the number of intermediates manageable: the change in bonding is limited to a maximum of two per steps and only changes to bonds involving "active atoms" (atoms with different bonding in reactants and products) are considered. Identifying active atoms involves mapping reactant atoms to product atoms, using the method proposed by Floudas and co-workers.  The AC matrices are converted to SMILES strings and 3D coordinates to ensure that they correspond to chemically reasonable molecules.

3. A reaction network is then constructed by finding intermediates that best connect reactants and products by computing "chemical distances (CDs)" between AC matrices and identifying intermediates with CDs to reactant and product that are similar to the CD between the reactant and product themselves. The CDs are then used to find the shortest path to reactant and product for each intermediate to yields a minimal reaction network.

4. Finally, TSs connecting the structures in the minimal reaction are found using conventional QM methods.

The method is applied to Claisen ester condensation and Cobalt-catalyzed hydroformylation. The method is implemented in a python program called ACE-Reaction but the availability of this program is unclear.  

Wednesday, December 13, 2017

A Zwitterionic, 10 π Aromatic Hemisphere

Hafezi, N.; Shewa, W. T.; Fettinger, J. C.; Mascal, M., Angew. Chem. Int. Ed. 2017, 56, 14141-14144
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

The range of aromatic compounds seems limitless. Mascal and co-workers have prepared the azatriquinacene 1 in a remarkably simple fashion.1 The molecule is a zwitterion, with the carbon atoms forming a 9-center, but 10 π-electron ring, and the quaternary nitrogen sitting above it. The carbon ring satisfies Hückel’s rule (4n+2) and so should be aromatic. The capping nitrogen should help to keep the carbon ring fixed in a shallow bowl.


As expected, the molecule in fact turns out to possess an aromatic 10 π-electron ring. The B3LYP/6-311++G(d,p) geometry is shown in Figure 1. There is little bond alternation among the C-C distances: the mean deviation is only 0.015 Å with the largest difference only 0.024 &Aring. The x-ray crystal structure shows the same trends. The NICS(1) value is -12.31 ppm, larger even than that of benzene (-10.22 ppm).

Figure 1. B3LYP/6-311++G(d,p) geometry of 1.


References

1) Hafezi, N.; Shewa, W. T.; Fettinger, J. C.; Mascal, M., "A Zwitterionic, 10 π Aromatic Hemisphere." Angew. Chem. Int. Ed. 201756, 14141-14144, DOI: 10.1002/anie.201708521.


InChIs

1: InChI=1S/C10H9N/c1-11-8-2-3-9(11)6-7-10(11)5-4-8/h2-7H,1H3
InChIKey=ZXZPLDVSQUVKTH-UHFFFAOYSA-N

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Monday, December 11, 2017

Heavy-Atom Tunneling Calculations in Thirteen Organic Reactions: Tunneling Contributions are Substantial, and Bell’s Formula Closely Approximates Multidimensional Tunneling at ≥250 K

Doubleday, C.; Armas, R.; Walker, D.; Cosgriff, C. V.; Greer, E. M., Angew. Chem. Int. Ed. 2017, 56, 13099-13102
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

Though recognized to occur in organic systems, the breadth of involvement of heavy-atom tunneling has not been established. Doubleday, Greer and coworkers have examined 13 simple organic reactions sampling pericyclic reactions, radical rearrangements and SN2 reactions for heavy-atom tunneling.1 A few of these reactions are shown below.

Reaction rates were obtained using the small curvature tunneling approximation (SCT), computed using Gaussrate. Reaction surfaces were computed at B3LYP/6-31G*. The tunneling correction to the rate was also estimated using the model developed by Bell: kBell = (u/2)/sin(u/2) where u = hν/RT and ν is the imaginary frequency associated with the transition state. The temperature was chosen so as to give a common rate constant of 3 x 10-5 s-1. Interestingly, all of the examined reactions exhibited significant tunneling even at temperatures from 270-350 K (See Table 1). The tunneling effect estimated by Bell’s equation is very similar to that of the more computationally demanding SCT computation.

Table 1. Tunneling contribution to the rate constant
Reaction
% tunneling
35
17
28
95
CN + CH3Cl → CH3CN + Cl (aqueous)
45

This study points towards a much broader range of reactions that may be subject to quantum mechanical tunneling than previously considered.


References

1. Doubleday, C.; Armas, R.; Walker, D.; Cosgriff, C. V.; Greer, E. M., "Heavy-Atom Tunneling Calculations in Thirteen Organic Reactions: Tunneling Contributions are Substantial, and Bell’s Formula Closely Approximates Multidimensional Tunneling at ≥250 K." Angew. Chem. Int. Ed. 2017, 56, 13099-13102, DOI: 10.1002/anie.201708489.



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Sunday, November 26, 2017

Understanding and Breaking Scaling Relations in Single-Site Catalysis: Methane-to-methanol Conversion by Fe(IV)=O

Highlighted by Jan Jensen




This is the first study I have come across that locates TS structures as part of a "high-throughput" single-site catalyst design study. Furthermore, the catalyst contains iron, which is not the easiest of elements to work with computationally. 

The study locates 76 and 43 TSs for the oxo formation (TS1) and hydrogen atom transfer (HAT, TS2) steps of the catalytic cycle. These are relatively small numbers compared to high throughput studies of other properties (hence the quotation marks), but they are roughly an order of magnitude larger than the number of TSs found in typical computational study of catalysts. The number is smaller for HAT due to difficulties in locating TSs for this step.

The TSs were located using either NEB implemented in DL-FIND or Q-CHEM where initial guess structures were generated using a locally modified version of molSimplify.

The studies show that there is a good correlation between reaction energy and barrier for the HAT step (R2 = 0.99) but a poor correlation for the oxo formation (R2 = 0.50 - 0.81). The authors conclude "Overall, our work shows that LFERs can be leveraged in single-site catalyst screening only when the coordination geometry is held fixed. Reliance solely on LFERs for single-site catalysis will thus miss rich areas of chemical space accessible through scaffold distortion."

Tuesday, November 14, 2017

Tunneling Control of Chemical Reactions: The Third Reactivity Paradigm

Schreiner, P. R., J. Am. Chem. Soc. 2017, 139, 15276-15283
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

Over the past nine years the Schreiner group, often in collaboration with the Allen group, have produced some remarkable studies demonstrating the role of tunneling control. (I have made quite a number of posts on this topics.) Tunneling control is a third mechanism for dictating product formation, in tandem with kinetic control (the favored product is the one that results from the lowest barrier) and thermodynamic control (the favored product is the one that has the lowest energy). Tunneling control has the favored product resulting from the narrowest mass-considered barrier.
Schreiner has written a very clear perspective on tunneling control. It is framed quite interestingly by some fascinating quotes:
It is probably fair to say that many organic chemists view the concept of tunneling, even of hydrogen atoms, with some skepticism. – Carpenter 19832
Reaction processes have been considered as taking place according to the laws of classical mechanics, quantum mechanical theory being only employed in calculating interatomic forces. – Bell 19333
Schreiner’s article makes it very clear how critical it is to really think about reactions from a truly quantum mechanical perspective. He notes the predominance of potential energy diagrams that focus exclusively on the relative energies and omits any serious consideration of the reaction coordinate metrics, like barrier width. When one also considers the rise in our understanding of the role of reaction dynamics in organic chemistry (see, for example, these many posts), just how long will it take for these critical notions to penetrate into standard organic chemical thinking? As Schreiner puts it:
It should begin by including quantum phenomena in introductory textbooks, where they are, at least in organic chemistry, blatantly absent. To put this oversight in words similar to those used much earlier by Frank Weinhold in a different context: “When will chemistry textbooks begin to serve as aids, rather than barriers, to this enriched quantum-mechanical perspective?”4


References

1) Schreiner, P. R., "Tunneling Control of Chemical Reactions: The Third Reactivity Paradigm." J. Am. Chem. Soc. 2017139, 15276-15283, DOI: 10.1021/jacs.7b06035.
2) Carpenter, B. K., "Heavy-atom tunneling as the dominant pathway in a solution-phase reaction? Bond shift in antiaromatic annulenes." J. Am. Chem. Soc. 1983105, 1700-1701, DOI: 10.1021/ja00344a073.
3) Bell, R. P., "The Application of Quantum Mechanics to Chemical Kinetics." Proc. R. Soc. London, Ser. A1933139 (838), 466-474, DOI: 10.1098/rspa.1933.0031.
4) Weinhold, F., "Chemistry: A new twist on molecular shape." Nature 2001411, 539-541, DOI: 10.1038/35079225.


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Tuesday, November 7, 2017

The Cope Rearrangement of 1,5-Dimethylsemibullvalene-2(4)-d1: Experimental Evidence for Heavy-Atom Tunneling

Schleif, T.; Mieres-Perez, J.; Henkel, S.; Ertelt, M.; Borden, W. T.; Sander, W., Angew. Chem. Int. Ed. 2017, 56, 10746-10749
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

Another prediction made by quantum chemistry has now been confirmed. In 2010, Zhang, Hrovat, and Borden predicted that the degenerate rearrangement of semibullvalene 1 occurs with heavy atom tunneling.1 For example, the computed rate of the rearrangement including tunneling correction is 1.43 x 10-3 s-1 at 40 K, and this rate does not change with decreasing temperature. The predicted half-life of 485 s is 1010 shorter than that predicted by transition state theory.
Now a group led by Sander has examined the rearrangement of deuterated 2.2 The room temperature equilibrium mixture of d42 and d22 was deposited at 3 K. IR observation showed a decrease in signal intensities associated with d42 and concomitant growth of signals associated with d22. The barrier for this interconversion is about 5 kcal mol-1, too large to be crossed at this temperature. Instead, the interconversion is happening by tunneling through the barrier (with a rate about 10-4 s-1), forming the more stable isomer d22 preferentially. This is exactly as predicted by theory!


References

1. Zhang, X.; Hrovat, D. A.; Borden, W. T., "Calculations Predict That Carbon Tunneling Allows the Degenerate Cope Rearrangement of Semibullvalene to Occur Rapidly at Cryogenic Temperatures." Org. Letters 2010, 12, 2798-2801, DOI: 10.1021/ol100879t.
2. Schleif, T.; Mieres-Perez, J.; Henkel, S.; Ertelt, M.; Borden, W. T.; Sander, W., "The Cope Rearrangement of 1,5-Dimethylsemibullvalene-2(4)-d1: Experimental Evidence for Heavy-Atom Tunneling." Angew. Chem. Int. Ed. 2017, 56, 10746-10749, DOI: 10.1002/anie.201704787.


InChIs

1: InChI=1S/C8H8/c1-3-6-7-4-2-5(1)8(6)7/h1-8H
InChIKey=VEAPRCKNPMGWCP-UHFFFAOYSA-N
d42: InChI=1S/C10H12/c1-9-5-3-7-8(4-6-9)10(7,9)2/h3-8H,1-2H3/i5D
InChIKey=WUJOLJNLXLACNA-UICOGKGYSA-N
d22: InChI=1S/C10H12/c1-9-5-3-7-8(4-6-9)10(7,9)2/h3-8H,1-2H3/i7D
InChIKey=WUJOLJNLXLACNA-WHRKIXHSSA-N


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