The nature of reactions of indolynes is the subject of two recent computational/experimental studies. There are three isomeric indolynes 1a-c which are analogues of the more famous benzyne (which I discuss in significant detail in Chapter 4.4 of my book).

One might anticipate that the indolynes undergo comparable reactions as benzyne, like Diels-Alder reactions and nucleophilic attack. In fact the indolynes do undergo these reactions, with unusual regiospecificity. For example, the reaction of the substituted 6,7-indolyne undergoes regioselective Diels-Alder cycloaddition with substituted furans (Scheme 1), but the reaction with the other indolynes gives no regioselection. ¹ Note that the preferred product is the more sterically congested adduct.

Scheme 1

In the case of nucleophilic addition, the nucleophiles add specifically to C₆ with substituted 6,7-indolynes (Scheme 2), while addition to 4,5-indolynes preferentially gives the C₅-adduct (greater than 3:1) while addition to the 5,6-indolynes preferentially gives the C₅-adduct), but with small selectivity (less than 3:1).²

Scheme 2

The authors of both papers – Chris Cramer studied the Diels-Alder chemistry and Ken Houk studied the nucleophilic reactions – employed DFT computations to examine the activation barriers leading to the two regioisomeric products. So for example, Figure 1 shows the two transition states for the reaction of 2c with 2-iso-propyl furan computed at MO6-2X/6-311+G(2df,p).

ΔG‡ = 9.7

ΔG‡ = 7.6

Figure 1. MO6-21/6-311+G(2df,p) optimized TSs for the reaction of 2-iso-propylfuran with 2c. Activation energy (kcal mol^-1) listed below each structure.¹

The computational results are completely consistent with the experiments. For the Diels-Alder reaction of 2-t-butylfuran with the three indolynes 2a-c, the lower computed TS always corresponds with the experimentally observed major product. The difference in the energy of the TSs leading to the two regioisomers for reaction with 2a and 2b is small (less than 1 kcal mol^-1), consistent with the small selectivity. On the other hand, no barrier could be found for the reaction of 2-t-butylfuran with 2c that leads to the major product. Similar results are also obtained for the nucleophilic addition – in all cases, the experimentally observed major product corresponds with the lower computed activation barrier.

So what accounts for the regioselectivity? Both papers make the same argument, though couched in slightly different terms. Houk argues in terms of distortion energy – the energy needed to distort reactants to their geometries in the TS. As seen in Figure 2, the benzyne fragment of 2a is distorted, with the C-C-C angle at C₄ of 125° and at C₅ of 129°. In the transition states, the angle at the point of nucleophilic attack widens. Since the angle starts out wider at C₅, attack there is preferred, since less distortion is needed to achieve the geometry of the TS.

2a
TS at C4 ΔG‡ = 12.9	TS at C5 ΔG‡ = 9.9

Figure 2. B3LYP/6-31G(d) optimized structures of 2a and the TSs for the reaction of aniline with 2a. Activation energy in kcal mol^-1.²

Cramer argues in terms of the indolyne acting as an electrophile. Increasing substitution at the furan 2-position makes is better at stabilizing incipient positive charge that will build up there during a (very) asymmetric Diels-Alder transition state. This explains the increasing selectivity of the furan with increasing substitution. The indolyne acting as an electrophile means that the attack will lead from the center will lesser charge. In 2c, the C-C-C angle at C₆ is 135.3°, while that at C₇ is 117.2°. This makes C₇ more carbanionic and C₆ more carbocationic; therefore, the first bond made is to C₆, leading to the more sterically congested product. Note that Houk’s argument applies equally well, as C₆ is predistorted to the TS geometry.

References

(1) Garr, A. N.; Luo, D.; Brown, N.; Cramer, C. J.; Buszek, K. R.; VanderVelde, D., "Experimental and Theoretical Investigations into the Unusual Regioselectivity of 4,5-, 5,6-, and 6,7-Indole Aryne Cycloadditions," Org. Lett., 2010, 12, 96-99, DOI: 10.1021/ol902415s

(2) Cheong, P. H. Y.; Paton, R. S.; Bronner, S. M.; Im, G. Y. J.; Garg, N. K.; Houk, K. N., "Indolyne and Aryne Distortions and Nucleophilic Regioselectivites," J. Am. Chem. Soc., 2010, 132, 1267-1269, DOI: 10.1021/ja9098643

InChIs

1a: InChI=1/C8H5N/c1-2-4-8-7(3-1)5-6-9-8/h2,4-6,9H
InChIKey=RNDHGGYOIRREHC-UHFFFAOYAU

1b: InChI=1/C8H5N/c1-2-4-8-7(3-1)5-6-9-8/h3-6,9H
InChIKey=WWZQFJXNXMIWCD-UHFFFAOYAO

1c: InChI=1/C8H5N/c1-2-4-8-7(3-1)5-6-9-8/h1,3,5-6,9H
InChIKey=UHIRLIIPIXHWLT-UHFFFAOYAH

2a: InChI=1/C9H7N/c1-10-7-6-8-4-2-3-5-9(8)10/h3,5-7H,1H3
InChIKey=VTVUPAJGRVFCKI-UHFFFAOYAJ

2b: InChI=1/C9H7N/c1-10-7-6-8-4-2-3-5-9(8)10/h4-7H,1H3
InChIKey=KKPOWDDYMOXTFW-UHFFFAOYAN

2c: InChI=1/C9H7N/c1-10-7-6-8-4-2-3-5-9(8)10/h2,4,6-7H,1H3
InChIKey=MDAHOGWZOBLIEX-UHFFFAOYAZ

So yesterday mornings “Future of Scholarly Publishing” was quite interesting. Steve Heller gave his usual enjoyable presentation of InChI and the InChI Trust. The establishment of the Trust ensures that progress and technical support for InChI continues on.

Alex Wade from Microsoft gave a great overview of the activities Microsoft has ongoing in the area of scholarly communication. I was impressed if not even overwhelmed with all that Microsoft is doing. If you were worried about Microsoft taking over the world, then this talk will only reinforce that concern! I will post a link to his talk once it is made available. UPDATE: Here is Alex’s PowerPoint presentation.

Next was Peter Murray-Rust, and this was a typical Peter talk. He started off by truly going after all scientific publishers for restrictions to and copyright notices plastered all over supplementary materials. These materials are almost exclusively data, and data cannot be copyrighted. Peter pleaded with publishers to allow free and unrestricted access to these materials and I wholeheartedly second this! Peter then demonstrated a number of chemistry semantic tools. His talk will be posted online, and I’ll get the URL here when it’s available.

The last of the talks I was able to see before leaving for the airport was by Joe Townsend. He demonstrated the new Chem4Word plugin (now rebranded “Chemistry Add-in for Word”). This tool allows for chemistry semantics to be placed into a docx file, with all chemistry preserved as xml. This is an amazing first step towards providing authors the proper tools to create data- and chemistry-rich documents that preserve chemical knowledge for distribution and archiving. The plugin is available here, and is only applicable for Word 2007, and that poses an interesting problem as pointed out during the Q&A session – ACS pubs cannot accept docx files, so all that semantics will be lost. As was mentioned in the talk, that’s data destruction, and it’s time for authors and readers to demand better from the STM publishers!

Not particularly strong programming at the year’s spring ACS meeting – but one great session in the organic division yesterday. This was the awards session in honor of John Baldwin getting the James Flack Norris Award for physical organic chemistry.

First to speak was James Duncan, who discussed his recent CASSCF computations looking for pseudopericylic [3,3]-sigmatropic migrations. I will be commenting on his latest work in a post that will appear soon.

I had to skip the next talk, but came back to hear John Brauman discuss recent work on the solvation effect in the S_N2 reaction. This is an interesting case of where the screening of larger substituents is counterbalanced by geometric changes that lead to greater charge distribution. The net effect is that they cancel each other out, and the methyl,ethyl, iso-propyl, butyl β-effect is negligible.

Next was Peter Schreiner who discussed his carbene work, specifically the enormous tunneling effect observed in hydroxymethylene (see this post). He discussed some new work, that is if anything even more fantastic on methylhydroxycarbene – look for this work perhaps later in 2011.

Last to speak was John Baldwin – and he described his truly tour de force efforts in examining the [1,3]-rearrangements of vinylcyclopropane and vinylcyclobutane. The former work is described in my book, while the later study is still ongoing.

John’s work is amazingly painstaking and careful. I am truly in awe of his dedication in taking on extremely difficult studies that require enormous care. John has really taught us a lot – not just about these rearrangements (they involve diradicals on a flat plateau demanding dynamic analysis – but how to think about a study and then carry it out to fruition so that all details are assessed. A truly deserving recipient!

Here’s another attempt (almost successful!) in creating a planar cyclooctatetraene. Nishininaga and Iyoda have fused silicon and sulfur bridges to the COT framework, hoping to force the 8-member ring out of its preferred tub-shape into a planar structure.¹ They report the synthesis of 1, 2, and 3b along with their x-ray structures. They also calculated the structures at B3LYP/6-31G(d,p) for 1-4 , and these optimized structures are shown in Figure 1.

1 18° 19°	2 3.0° 4.3°
3a 7.0° (for 3b) 3.2° (for 3a)	4 39° 40°

Figure 1. B3LYP/6-31G(d,p) optimized geometries of 1-4. The experimental (top) and computed (Bottom in italics) value of α are listed for each compound.¹

The bent angle α is defined at the angle between the two planes that define the bottom of the tub and one of the sides. For COT itself, this angle is 40°, decidedly non-planar – as expected for a molecule avoiding the antiaromatic character it would have in its planar conformation. The computed and experimental values of α are shown in Figure 1. 4 is tub shaped. The value of α for 1 is about 18° – still tub shaped but flattened. But 2 and 3 are nearly planar, with experimental values of α about 3° and the computed values are similar.

So what is the character of the 8-member ring in these compounds. The computed NICS(0) values are 3.8 ppm for 4, the expected small value for a non-aromatic compound. (Note that the NICS value for COT is 2.9 ppm.) The values are much more positive for the other compounds: 12.7 ppm for 1, 17.4 ppm for 2, and 15.4 ppm for 3a. These compounds therefore display antiaromatic character yet they are isolable compounds!

References

(1) Ohmae, T.; Nishinaga, T.; Wu, M.; Iyoda, M., "Cyclic Tetrathiophenes Planarized by Silicon and Sulfur Bridges Bearing Antiaromatic Cyclooctatetraene Core: Syntheses, Structures, and Properties," J. Am. Chem. Soc., 2009, 132, 1066-1074, DOI: 10.1021/ja908161r

InChIs

1: InChI=1/C20H16S4Si2/c1-25(2)9-5-21-17-13(9)14-10(25)6-22-18(14)20-16-12(8-24-20)26(3,4)11-7-23-19(17)15(11)16/h5-8H,1-4H3/b19-17-,20-18-
InChIKey=DAVVQYAXJVCICC-CLFAGFIQBV

2: InChIKey=PBXVOLKKILUEGI-RFIZXXDFBX

3a: InChI=1/C16H4O4S6/c17-25(18)5-1-21-13-9(5)10-6(25)2-23-15(10)16-12-8(4-24-16)26(19,20)7-3-22-14(13)11(7)12/h1-4H/b14-13-,16-15-
InChIKey=VIDZCGPUBZEACC-RFIZXXDFBR

3b: InChI=1/C28H36O4S6Si4/c1-39(2,3)25-21-13-14-19(35-26(40(4,5)6)22(14)37(21,29)30)20-16-15-18(17(13)33-25)34-27(41(7,8)9)23(15)38(31,32)24(16)28(36-20)42(10,11)12/h1-12H3/b18-17-,20-19-
InChIKey=XXCFCYWSFICMIO-RXGVRZIVBS

4: InChI=1/C16H8S4/c1-5-17-13-9(1)10-2-6-18-14(10)16-12(4-8-20-16)11-3-7-19-15(11)13/h1-8H/b10-9-,12-11-,15-13-,16-14-
InChIKey=RSNUTSCZGMAXQJ-FNJUYVFOBD

The keto-enol tautomerization is an interesting system for probing relative energies of subtle effects, playing off different bond type (and their associated strengths) with conjugation and hydrogen bonding and strain. Lawrence and Hutchings have now extended this to include the interplay of aromaticity and antiaromaticity in the keto-enol tautomerization of benzodifurantrione 1.¹ The keto form 1k looks to be the favotable tautomer, containing an aromatic phenyl ring. The enol tautomer 1e requires the loss of that aromatic ring. Nonetheless, the enol structure is the only tautomer present in the crystal phase, and the enol tautomer is the dominant structure (if not the exclusive structure) in all solvents tested, including acetic acid, acetone, acetonitrile, chloroform, DMF, DMSO, propanol and toluene. The only solvents where the keto form is dominant are toluene and o-dichlorobenzene.

So, how does one rationalize this equilibrium? The B3LYP/6-311G(2d,p) structure of the two tautomers are shown in Figure 1. Note that there are two isomers of the enol form, differing on the orientation of the hydroxyl hydrogen. The syn isomer is the lowest energy form, in both the gas phase and in solution (PCM modeling acetonitrile, chlorobenzene and THF). So the enol form is the lowest energy structure when there are no special interactions involving hydrogen bonding or dipolar interactions with the solvent – there is an inherent energy preference for 1e.

1k
1e-anti	1e-syn

Figure 1. B3LYP/6-311G(2d,p) structures of the tautomers of 1.¹

To address that, they computed the NICS(0) values for each ring in the two tautomers. The pendant phenyl group is aromatic in both structures, as expected. The lactone ring has NICS values near 0 in both structures. The interior phenyl ring is aromatic (NICS = -7.5) in 1k but is non-aromatic in 1e, with NICS=-0.4. So the aromaticity of this ring is lost upon enolization, and thus would favor 1k. However, the terminal ring in the keto tautomer has NICS = +7.2, suggesting that it is antiaromatic, and upon enolization, the ring becomes slightly aromatic, with NICS = -2.1. Thus, the keto form is plagued by an antiaromatic ring, which is then lost in the enol form. The result is the interplay between losing an aromatic ring and its stabilization when the enol is formed balanced by also losing an antiaromatic ring with its destabilization. The authors do not offer any quantization (rightfully so!) of the stabilization/destabilization associated with these rings. But very subtle effects are clearly at play.

References

(1) Lawrence, A. J.; Hutchings, M. G.; Kennedy, A. R.; McDouall, J. J. W., "Benzodifurantrione: A Stable Phenylogous Enol," J. Org. Chem., 2010, 75, 690–701, DOI: 10.1021/jo9022155

InChIs

1k: InChI=1/C16H8O5/c17-14-10-7-11-9(6-12(10)21-16(14)19)13(15(18)20-11)8-4-2-1-3-5-8/h1-7,13H
InChIKey=GNWKSKHSRUSFBC-UHFFFAOYAC

1e: InChI=1/C16H8O5/c17-14-10-7-11-9(6-12(10)21-16(14)19)13(15(18)20-11)8-4-2-1-3-5-8/h1-7,17H
InChIKey=MZLQKOSFMRKQIO-UHFFFAOYAB

Houk has performed a very nice examination of the performance of some density functionals.¹ He takes a quite different approach than what was proposed by Grimme – the “mindless” benchmarking² using random molecules (see this post). Rather, Houk examined a series of simple aldol, Mannich and α-aminoxylation reactions, comparing their reaction energies predicted with DFT against that predicted with CBQ-QB3. The idea here is to benchmark DFT performance for simple reactions of specific interest to organic chemists. These reactions are of notable current interest due their involvement in organocatalytic enantioselective chemistry (see my posts on the aldol, Mannich, and Hajos-Parrish-Eder-Sauer-Wiechert reaction). Examples of the reactions studied (along with their enthalpies at CBS-QB3) are Reaction 1-3.

For the four simple aldol reactions and four simple Mannich reactions, PBE1PBE,
mPW1PW91 and MO6-2X all provided reaction enthalpies with errors of about 2 kcal mol^-1. The much maligned B3LYP functional, along with B3PW91 and B1B95 gave energies with significant larger errors. For the three α-aminoxylation reactions, the errors were better with B3PW91 and B1B95 than with PBE1PBE or MO6-2X. Once again, it appears that one is faced with finding the right functional for the reaction under consideration!

Of particular interest is the decomposition of these reactions into related isogyric, isodesmic
and homdesmic reactions. So for example Reaction 1 can be decomposed into Reactions 4-7 as shown in Scheme 1. (The careful reader might note that these decomposition reactions are isodesmic and homodesmotic and hyperhomodesmotic reactions.) The errors for Reactions 4-7 are typically greater than 4 kcal mol^-1 using B3LYP or B3PW91, and even with MO6-2X the errors are about 2 kcal mol^-1.

Scheme 1.

Houk also points out that Reactions 4, 8 and 9 (Scheme 2) focus on having similar bond changes as in Reactions 1-3. And it’s here that the results are most disappointing. The errors produced by all of the functionals for Reactions 4,8 and 9 are typically greater than 2 kcal mol^-1, and even MO2-6x can be in error by as much as 5 kcal mol^-1. It appears that the reasonable performance of the density functionals for the “real world” aldol and Mannich reactions relies on fortuitous cancellation of errors in the underlying reactions. Houk calls for the development of new functionals designed to deal with fundamental simple bond changing reactions, like the ones in Scheme 2.

Scheme 2

References

(1) Wheeler, S. E.; Moran, A.; Pieniazek, S. N.; Houk, K. N., "Accurate Reaction Enthalpies and Sources of Error in DFT Thermochemistry for Aldol, Mannich, and α-Aminoxylation Reactions," J. Phys. Chem. A 2009, 113, 10376-10384, DOI: 10.1021/jp9058565

(2) Korth, M.; Grimme, S., ""Mindless" DFT Benchmarking," J. Chem. Theory Comput. 2009, 5, 993–1003, DOI: 10.1021/ct800511q