Archive for December, 2009

Enantioselective Michael Addition

Coming on the heels of the very nice combined computational/experimental study of the enantioselective Strecker reaction by Jacobsen (see this post), there’s this JACS communication that really disappoints in its use of computational chemistry. Cobb uses yet another chiral thiourea to produce the enantioselective intramolecular Michael addition of nitronoates (Reaction1).1 The reaction goes with excellent diastereoselectivity and eneatioselectivity, and can even be done with a substrate to produce three chiral centers. This is very nice synthetic chemistry.

Reaction 1.

dr >19:1
ee 95%

The lack of reactivity of the Z ester suggested that the thiourea must associate with both the nitro group and the ester carbonyl. The authors provide a B3LYP/3-21G complex of thiourea with a simple nitroester (once again without providing coordinates in the supporting materials!) to demonstrate this sort of association. But this single structure, at this very low computational level, with these simplified reagents, and lacking solvent (see Rzepa’s comment) really makes one wonder just what value this computation provides. It also goes to demonstrate just how much effort Jacobsen went through to provide substantive computational support for his proposed mechanism of action.


(1) Nodes, W. J.; Nutt, D. R.; Chippindale, A. M.; Cobb, A. J. A., "Enantioselective Intramolecular Michael Addition of Nitronates onto Conjugated Esters: Access to Cyclic γ-Amino Acids with up to Three Stereocenters," J. Am. Chem. Soc. 2009, 131, 16016-16017, DOI: 10.1021/ja9070915

Michael addition Steven Bachrach 21 Dec 2009 1 Comment

Garrat-Braverman vs Myers-Saito Cyclization

The competition between Bergman cyclization and Myers-Saito cyclization of ene-ynes and related species is discussed in Chapter 3.3 of my book and also in these posts. Yet another variation, the Garratt-Braverman cyclization1-3 has now been examined in terms of competition with the Myers-Saito cyclization for 1 using both experiments and computations.4 Subjecting 1 to base should cause the rearrangement to either GB1 or MS2. These can undergo either the Garratt-Braverman cyclization to give GB2 or the Myers-Saito cyclization to MS2.

B3LYP/6-31G(d) predicts that GB1 is only slightly higher in energy than MS1 (by 0.7 kcal mol-1). The transition states (GB1toGB2 or MS1toMS2 – see Figure 1) each lie 24.4 kcal mol-1 above their respective reactants. However, the diradical GB2 is 7.2 kcal mol-1 below GB1 but MS2 is only 0.3 kcal mol-1 below MS1. So while the two reactions are of similar kinetic probability, having identical activation barriers, the GB route leads to the more thermodynamically stable intermediate. Furthermore, the GB route ultimately results in GBP, via an intramolecular cyclization of the diradical, while the MS route, which ends with MSP, requires intermolecular abstraction of 4 hydrogens. Thus, the unimolecularity of the GB path further favors the GB route over the MS pathway. In fact, experimental studies of 1 and related compounds all give rise to the GB product only.







Figure 1. B3LYP/6-31G(d) optimized structures.4


(1) Braverman, S.; Segev, D., "Novel cyclization of diallenic sulfones," J. Am. Chem. Soc. 2002, 96, 1245-1247, DOI: 10.1021/ja00811a060

(2) Garratt, P. J.; Neoh, S. B., "Strained heterocycles. Properties of five-membered heterocycles fused to four-, six-, and eight-membered rings prepared by base-catalyzed rearrangement of 4-heterohepta-1,6-diynes," J. Org. Chem. 2002, 44, 2667-2674, DOI: 10.1021/jo01329a016

(3) Zafrani, Y.; Gottlieb, H. E.; Sprecher, M.; Braverman, S., "Sequential Intermediates in the Base-Catalyzed Conversion of Bis(π-conjugated propargyl) Sulfones to 1,3-Dihydrobenzo- and Naphtho[c]thiophene-2,2-dioxides," J. Org. Chem. 2005, 70, 10166-10168, DOI: 10.1021/jo051692i

(4) Basak, A.; Das, S.; Mallick, D.; Jemmis, E. D., "Which One Is Preferred: Myers-Saito Cyclization of Ene-Yne-Allene or Garratt-Braverman Cyclization of Conjugated Bisallenic Sulfone? A Theoretical and Experimental Study," J. Am. Chem. Soc. 2009, 131, 15695-15704, DOI: 10.1021/ja9023644

Bergman cyclization Steven Bachrach 14 Dec 2009 No Comments

Oxyallyl diradical

The longstanding unknown oxyallyl diradical (1) singlet-triplet gap has now been addressed with a very nice photoelectron spectroscopy study by Lineberger with interpretation greatly aided by computations provided by Hrovat and Borden.1

The photoelectron detachment spectrum of oxyallyl radical anion shows 5 major peaks, one at 1.942 eV and a series of four peaks starting at 1.997 eV separated by 405 cm-1.

B3LYP/6-311++G(d,p) computations indicate that the energy for electron detachment from the radical anion to triplet oxyallyl diradical is 1.979 eV. (The structure of triplet 1 is shown in Figure 1.) Further, the computed vibrational frequency of the C-C-C bend is 408 cm-1. These computations suggest that the four peak sequence represents a vibrational progression in the C-C-C bend of the triplet oxyallyl diradical.



Figure 1. Structures of the singlet and triplet oxyallyl diradical 1.1

CASPT2 computations on singlet oxyallayl diradical indicate that it lies in a very shallow well, lower than the zero-point energy. (This structure is shown in Figure 1.) In fact, the singlet diradical can collapse without a barrier to cyclopropanone. Interestingly, the C-O stretching frequency of 1 is computed to be 1731 cm-1, and close inspection of the photoelectron spectrum does show a progression of this magnitude originating from peak A. Therefore, both the singlet and triplet states of 1 are identified and their gap is extraordinarily small – the singlet is only 0.055 eV lower in energy than the triplet.


(1) Ichino, T.; Villano, S. M.; Gianola, A. J.; Goebbert, D. J.; Velarde, L.; Sanov, A.; Blanksby, S. J.; Zhou, X.; Hrovat, D. A.; Borden, W. T.; Lineberger, W. C., "The Lowest Singlet and Triplet States of the Oxyallyl Diradical," Angew. Chem. Int. Ed., 2009, 48, 8509-8511, DOI: 10.1002/anie.200904417

Borden &diradicals Steven Bachrach 07 Dec 2009 No Comments