Archive for the 'Houk' Category

Dynamics in the reaction of tetrazine with cyclopropene

Houk and Doubleday report yet another example of dynamic effects in reactions that appear to be simple, ordinary organic reactions.1 Here they look at the Diels-Alder reaction of tetrazine 1 with cyclopropene 2. The reaction proceeds by first crossing the Diels-Alder transition state 3 to form the intermediate 4. This intermediate can then lose the anti or syn N2, through 5a or 5s, to form the product 6. The structures and relative energies, computed at M06-2X/6-31G(d), of these species are shown in Figure 1.






Figure 1. M06-2X/6-31G(d) optimized geometries and energies (relative to 1 + 2) of the critical points along the reaction of tetrazine with cyclopropene.

The large difference in the activation barriers between crossing 5a and 5s (nearly 9 kcal mol-1) suggests, by transition state theory, a preference of more than a million for loss of the anti N2 over the syn N2. However, quasiclassical trajectory studies, using B3LYP/6-31G(d), finds a different situation. The anti pathway is preferred, but only by a 4:1 ratio! This dynamic effect arises from a coupling of the v3 mode which involves a rocking of the cyclopropane ring that brings a proton near the syn N2 functionality, promoting its ejection. In addition, the trajectory studies find short residence times within the intermediate neighborhood for the trajectories that lead to the anti product and longer residence times for the trajectories that lead to the syn product. All together, a very nice example of dynamic effects playing a significant role in a seemingly straightforward organic reaction.


(1) Törk, L.; Jiménez-Osés, G.; Doubleday, C.; Liu, F.; Houk, K. N. "Molecular Dynamics of the Diels–Alder Reactions of Tetrazines with Alkenes and N2 Extrusions from Adducts," J. Am. Chem. Soc. 2015, 137, 4749-4758, DOI: 10.1021/jacs.5b00014.


1: InChI=1S/C2H2N4/c1-3-5-2-6-4-1/h1-2H

2: InChI=1S/C3H4/c1-2-3-1/h1-2H,3H2

4: InChI=1S/C5H6N4/c1-2-3(1)5-8-6-4(2)7-9-5/h2-5H,1H2

6: InChI=1S/C5H6N2/c1-4-2-6-7-3-5(1)4/h2-5H,1H2

Diels-Alder &Dynamics &Houk Steven Bachrach 09 Nov 2015 No Comments

Dyotropic rearrangement

Houk and Vanderwal have examined the dyotropic rearrangement of an interesting class of polycyclic compounds using experimental and computational techniques.1 The parent reaction takes the bicyclo[2.2.2]octadiene 1 into the bicyclo[3.2.1]octadiene 3. The M06-2X/6-311+G(d,p)/B3LYP/6-31G(d) (with CPCM simulating xylene) geometries and relative energies are shown in Figure 1. The calculations indicate a stepwise mechanism, with an intervening zwitterion intermediate. The second step is rate determining.






Figure 1. B3LYP/6-31G(d) and relative energies (kcal mol-1) at M06-2X/6-311+G(d,p).

Next they computed the activation barrier for the second TS for a series of substituted analogs of 1, with various electron withdrawing group as R1 and electron donating groups as R2, and compared them with the experimental rates.

Further analysis was done by relating the charge distribution in these TSs with the relative rates, and they find a nice linear relationship between the charge and ln(krel). This led to the prediction that a cyano substituent would significantly activate the reaction, which was then confirmed by experiment. Another prediction of a rate enhancement with Lewis acids was also confirmed by experiment.

A last set of computations addressed the question of whether a ketone or lactone would also undergo this dyotropic rearrangement. The lactam turns out to have the lowest activation barrier by far.


(1) Pham, H. V.; Karns, A. S.; Vanderwal, C. D.; Houk, K. N. "Computational and Experimental Investigations of the Formal Dyotropic Rearrangements of Himbert Arene/Allene Cycloadducts," J. Am. Chem. Soc. 2015, 137, 6956-6964, DOI: 10.1021/jacs.5b03718.


1: InChI=1S/C11H11NO/c1-12-10(13)7-9-6-8-2-4-11(9,12)5-3-8/h2-5,7-8H,6H2,1H3

3: InChI=1S/C11H11NO/c1-12-10(13)6-9-3-2-8-4-5-11(9,12)7-8/h2-6,8H,7H2,1H3

Houk Steven Bachrach 29 Jun 2015 1 Comment

Molecular rotor and C-Hπ interaction

Molecular rotors remain a fascinating topic – the idea of creating a miniature motor just seems to capture the imagination of scientists. Garcia-Garibay and his group have synthesized the interesting rotor 1, and in collaboration with the Houk group, they have utilized computations to help understand the dynamics of this rotor.1


The x-ray structure of this compound, shown in Figure 1, displays two close interactions of a hydrogen on the central phenyl ring with the face of one of the steroidal phenyl rings. Rotation of the central phenyl ring is expected to then “turn off” one or both of these C-Hπ interactions. The authors argue this as a competition between the molecule sampling an enthalpic region, where the molecule has one or two favorable C-Hπ interactions, and the large entropic region where these C-Hπ interactions do not occur, but this space is expected to have a large quantity of energetically similar conformations.




Figure 1. X-ray and M06-2x/6-31G(d) optimized structures of 1.

Variable temperature NMR finds the central phenyl hydrogen with a chemical shift of 6.55ppm at 295 K but at 6.32 ppm at 222 K. This suggest as freezing of the conformations at low temperature favoring those conformations possessing the internal C-Hπ interactions. M06-2X/6-31G(d) optimization finds two low-energy conformations with a single C-Hπ interaction. These are shown in Figure 1. No competing conformation was found to have two such interactions. Computations of the chemical shifts of these conformations show the upfield shift of the central phenyl hydrogens. Fitting these chemical shifts to the temperature data gives ΔH = -1.74 kcal mol-1, ΔS = -5.12 esu and ΔG = -0.21 kcal mol-1 for the enthalpic region to entropic region transition.


(1) Pérez-Estrada, S.; Rodrı́guez-Molina, B.; Xiao, L.; Santillan, R.; Jiménez-Osés, G.; Houk, K. N.; Garcia-Garibay, M. A. "Thermodynamic Evaluation of Aromatic CH/π Interactions and Rotational Entropy in a Molecular Rotor," J. Am. Chem. Soc. 2015, 137, 2175-2178, DOI: 10.1021/ja512053t.


1: InChI=1S/C48H54O4/c1-45-23-19-39-37-15-11-35(51-3)29-33(37)9-13-41(39)43(45)21-27-47(45,49)25-17-31-5-7-32(8-6-31)18-26-48(50)28-22-44-42-14-10-34-30-36(52-4)12-16-38(34)40(42)20-24-46(44,48)2/h5-8,11-12,15-16,29-30,39-44,49-50H,9-10,13-14,19-24,27-28H2,1-4H3

Aromaticity &Houk &Hydrogen bond Steven Bachrach 23 Mar 2015 No Comments

Two review articles for the general audience

In trying to clean up my in-box of articles for potential posts, I write here about two articles for a more general audience, authored by two of the major leaders in computational organic chemistry.

Ken Houk offers an overview of how computational simulation is a partner with experiment and theory in aiding and guiding our understanding of organic chemistry.1 The article is written for the non-specialist, really even more for the non-scientist. Ken describes how computations have helped understand relatively simple reactions like pericyclic reactions, that then get more subtle when torquoselection is considered, to metal-catalysis, to designed protein catalysts. If you are ever faced with discussing just what you do as a computational chemist at a cocktail party, this article is a great resource of how to explain our science to the interested lay audience.

Paul Schleyer adds a tutorial on transition state aromaticity.2 The authors discusses a variety of aromaticity measures (energetics, geometry, magnetic properties) that can be employed to analyze the nature of transition states, in addition to ground state molecules. This article provides a very clear description of the methods and a few examples. It is written for a more specialized audience than Houk’s article, but is nonetheless completely accessible to any chemist, even those with no computational background.


(1) Houk, K. N.; Liu, P. "Using Computational Chemistry to Understand & Discover Chemical Reactions," Daedalus 2014, 143, 49-66, DOI: 10.1162/DAED_a_00305.

(2) Schleyer, P. v. R.; Wu, J. I.; Cossio, F. P.; Fernandez, I. "Aromaticity in transition structures," Chem. Soc. Rev. 2014, 43, 4909-4921, DOI: 10.1039/C4CS00012A.

Houk &Schleyer Steven Bachrach 22 Dec 2014 No Comments

Diels-Alder reactions of Fullerene

Diels-Alder reaction involving fullerenes have been known for some time. They occur across the [6,6] double bond of C60, the one between two fused 6-member rings. Houk and Briseno report on the Diels-Alder reaction of C60 with pentacene 1 and bistetracene 2 and compare their computations with experiments.1

Pentacene and bistetracene ring numbering convention

Computations were performed for the reaction of 1 and 2 with C60 at M06-2x/6-31G(d)//M062x-3-21G*. The reaction can occur with the dienophile being either ring 1, 2, or 3 of pentacene and ring 1, 2, 3, or 4 of bistetracene. They located TSs and products for all of these possibilities. Select TSs and products are shown in Figure 1.

For the reaction of 1a, the lowest energy TS is for the reaction at the central ring (ring 3), and the resulting product is the lowest energy product. The transition state (PT_TS3) is shown in Figure 1. This TS has the least distortion energy of the three possibilities, because reacting at this central ring destroys the least amount of aromaticity of pentacene. For the reaction of 1b, the lowest barrier is again for reaction of ring 3 (through TMSPT_TS3). However, the product from the reaction with ring 2 (TMSPT_P2) is lower in free energy than TMSPT­_P3, likely caused by steric interactions with the silyl substituents. This actually matches up with experiments which indicate that an analogue of TMSPT_P2 is the kinetic product but TMSPT_P3 is the thermodynamic product.







Figure 1. M06-2x/3-21G* optimized geometries.
(Once again a reminder that clicking on any of these structures will launch JMol and you’ll be able to visualize and manipulate this structure in 3-D.)

The computations involving the Diels-Alder reaction of C60 with either 2a or 2b come to the same conclusion. In both cases, the lowest barrier is for the reaction at ring 2, and the product of the reaction at this same ring is the only one that is endoergonic. The geometries of BT_TS2 and BT_P2 are shown in Figure 1. More importantly, the barrier for the Diels-Alder reaction involving 2a and 2b are at least 6 kcal mol-1 higher than the barriers for the reaction of 1a and 1b, in complete agreement with experiments that show little reaction involving analogues of 2b with C60, while analogues of 1b are reasonably rapid.


(1) Cao, Y.; Liang, Y.; Zhang, L.; Osuna, S.; Hoyt, A.-L. M.; Briseno, A. L.; Houk, K. N. "Why Bistetracenes Are Much Less Reactive Than Pentacenes in Diels–Alder Reactions with Fullerenes," J. Am. Chem. Soc. 2014, 136, 10743-10751, DOI: 10.1021/ja505240e.

Diels-Alder &fullerene &Houk Steven Bachrach 29 Sep 2014 No Comments

Torqoselectivity in forming a Cis,Trans-Cyclooctadienone

Houk’s theory of torquoselectivity is a great achievement of computational chemistry, as told in Chapter 4.6 of the second edition of my book. Houk, in a collaboration with Krenske and Hsung, now report on an application of torquoselectivity in the formation of a cis-trans-cyclooctadienone intermediate.1

The proposed reaction is shown in Scheme 1, where the bicyclic compound undergoes a conrotatory ring opening in just one orientation to form the E,E-cyclooctadienone, which can then ring close to product.

Scheme 1.

Houk ran M06-2x//6-311+G(d,p)//B3LYP/6-31G(d) computations on the model system 1, passing over the two torquodistinctive transition states TSEE and TSZZ, and on to produce the two cyclooctadienones 2EE and 2ZZ, respectively. As seen in Figure 1, the barrier through TSEE is favored by 9.8 kcal mol-1, and leads to the much more favorable cycloocatadienone 2EE.







Figure 1. B3LYP/6-31G(d) optimized structures and relative free energies (kcal mol-1) at M06-2x//6-311+G(d,p)//B3LYP/6-31G(d).

Ring closure taking TSEE to product goes through TS2 (Figure 1), with a very high barrier, 47.5 kcal mol-1 above reactant, suggesting that this path is not likely to occur. Instead, they propose that 2EE is first protonated (2EEH+) and then cyclizes through TS2H+ (Figure 2). This barrier is only 6.2 kcal mol-1, some 44 kcal mol-1 lower than the neutral process through TS2.



Figure 2. B3LYP/6-31G(d) optimized structures


(1) Wang, X.-N.; Krenske, E. H.; Johnston, R. C.; Houk, K. N.; Hsung, R. P. "Torquoselective Ring Opening of Fused Cyclobutenamides: Evidence for a Cis,Trans-Cyclooctadienone Intermediate," J. Am. Chem. Soc. 2014, 136, 9802-9805, DOI: 10.1021/ja502252t.

Houk Steven Bachrach 11 Aug 2014 No Comments

The Click Reaction in Nature?

The click reaction has become a major workhorse of synthetic chemists since its proposal in 2001.1 Despite its efficiencies, no clear-cut example of its use in nature has been reported until 2012, where Yu and co-workers speculated that it might be utilized in the biosynthesis of lycojaponicumin A and B.2 Krenske, Patel, and Houk have examined the possibility of an enzyme activated click process in forming this natural product.3

First they examined the gas-phase intramolecular [3+2] reaction that takes 1 into 2.

They identified (at M06-2X/def2-TZVPP/M06-2X/6-31+G(d,p)) four different low-energy conformations of 1, of which three have the proper orientation for the cyclization to occur. The lowest energy conformer, the TS, and the product 2 are shown in Figure 1. The free energy activation barrier in the gas phase is 19.8 kcal mol-1. Inclusion of water as an implicit solvent (through a TS starting from a different initial conformation) increases the barrier to 20.0 kcal mol-1. Inclusion of four explicit water molecules, hydrogen bonded to the nitrone and enone, predicts a barrier of 20.5 kcal mol-1. These values predict a slow reaction, but not totally impossible. In fact, Tantillo in a closely related work reported a theoretical study of the possibility of a [3+2] cyclization in the natural synthesis of flueggine A and virosaine, and found barriers of comparable size as here. Tantillo concludes that enzymatic activation is not essential.4




Table 1. M06-2X/6-31+G(d,p) optimized geometries of 1, TS12, and 2.

To model a potential enzyme, the Houk group created a theozyme whereby two water molecules act as hydrogen bond donors to the enone and the use of implicit solvent (diethyl ether) to mimic the interior of an enzyme. This theozyme model predicts a barrier of 15.3 kcal mol-1, or a 2000 fold acceleration of the click reaction. The search for such an enzyme might prove quite intriguing.


(1) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. "Click Chemistry: Diverse Chemical Function from a Few Good Reactions," Angew. Chem. Int. Ed. 2001, 40, 2004-2021, DOI: 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5.

(2) Wang, X.-J.; Zhang, G.-J.; Zhuang, P.-Y.; Zhang, Y.; Yu, S.-S.; Bao, X.-Q.; Zhang, D.; Yuan, Y.-H.; Chen, N.-H.; Ma, S.-g.; Qu, J.; Li, Y. "Lycojaponicumins A–C, Three Alkaloids with an Unprecedented Skeleton from Lycopodium japonicum," Org. Lett. 2012, 14, 2614-2617, DOI: 10.1021/ol3009478.

(3) Krenske, E. H.; Patel, A.; Houk, K. N. "Does Nature Click? Theoretical Prediction of an Enzyme-Catalyzed Transannular 1,3-Dipolar Cycloaddition in the Biosynthesis of Lycojaponicumins A and B," J. Am. Chem. Soc. 2013, 135, 17638-17642, DOI: 10.1021/ja409928z.

(4) Painter, P. P.; Pemberton, R. P.; Wong, B. M.; Ho, K. C.; Tantillo, D. J. "The Viability of Nitrone–Alkene (3 + 2) Cycloadditions in Alkaloid Biosynthesis," J. Org. Chem. 2014, 79, 432–435, DOI: 10.1021/jo402487d.


1: InChI=1S/C16H21NO3/c1-11-8-12-10-14(18)13-4-2-6-17(20)7-3-5-16(12,13)15(19)9-11/h4,7,11-12H,2-3,5-6,8-10H2,1H3/b13-4-,17-7+

2: InChI=1S/C16H21NO3/c1-9-6-10-8-13(19)16-11(17-5-3-14(16)20-17)2-4-15(10,16)12(18)7-9/h9-11,14H,2-8H2,1H3/t9?,10-,11?,14?,15+,16-/m0/s1

cycloadditions &Houk Steven Bachrach 04 Feb 2014 No Comments

A stepwise Diels-Alder

Halskov, et al.1 reported the interesting Diels-Alder selectivity shown in Scheme 1. The linear trienamine 1 did not undergo the Diels-Alder addition, while the less stable cross-conjugated diene 2 does react with 3 with high diastereo- and enantioselectivity. Their MPW1K/6-31+G(d,p) computations on a model system, carried out for a gas-phase environment, indicated a concerted mechanism, with thermodynamic control. However, the barrier for the reverse reaction for the kinetic product was computed to be greater than 30 kcal mol-1, casting doubt on the possibility of thermodynamic control.

Scheme 1.

Houk and co-workers2 have re-examined this reaction with the critical addition of performing the computation including the solvent effects. Since the stepwise alternatives involve the formation of zwitterions, solvent can be critical in stabilizing these charge-separated species, intermediates that might be unstable in the gas phase. Henry Rzepa has pointed out in his blog and on many comments in this blog about the need to include solvent, and this case is a prime example of the problems inherent in neglecting solvation.

Using models of the above reaction Houk located two zwitterionic intermediates of the Michael addition for both the reactions of 4 with 6 and of 5 with 6. The second step then involves the closure of the ring to give what would be Diels-Alder products. This is shown in Scheme 2. They were unable to locate transition states for any concerted pathways. The computations were done at M06-2x/def2-TZVPP/IEFPCM//B97D/6-31+G(d,p)/IEFPCM, modeling trichloromethane as the solvent.

Scheme 2. Numbers in italics are energies relative to 4 + 6.

The activation barrier for the second step in each reaction is very small, typically less than 5 kcal mol-1, so the first step is rate determining. The lowest barrier is for the reaction of 5 leading to 9, analogous to the observed product. Furthermore, 9 is also the thermodynamic product. Thus, the regioselectivity is both kinetically and thermodynamically controlled through a stepwise reaction. This conclusion is only possible by including solvent in order to stabilize the zwitterionic intermediates, and should be a word of caution for everyone doing computations: be sure to include solvent for any reactions that involved charged or charge-separated species at any point along the reaction pathway!


(1) Halskov, K. S.; Johansen, T. K.; Davis, R. L.; Steurer, M.; Jensen, F.; Jørgensen, K. A. "Cross-trienamines in Asymmetric Organocatalysis," J. Am. Chem. Soc. 2012, 134, 12943-12946,
DOI: 10.1021/ja3068269.

(2) Dieckmann, A.; Breugst, M.; Houk, K. N. "Zwitterions and Unobserved Intermediates in Organocatalytic Diels–Alder Reactions of Linear and Cross-Conjugated Trienamines," J. Am. Chem. Soc. 2013, 135, 3237-3242, DOI: 10.1021/ja312043g.

Diels-Alder &Houk Steven Bachrach 02 Apr 2013 4 Comments

Proximity-induced Diels-Alder Reaction

The intramolecular Diels-Alder reaction of 1 occurs slowly, but quantitatively, at room temperature.1 This is unusual as most Diels-Alder cyclizations require heating to typically 200 °C. For example, the related cyclization of 2 requires heating to 170 °C.2 What is the cause for this proximity-induced reaction?

Reaction 1

Reaction 2

Reaction 3

Houk and Baran address this question using a computational approach.3 The Diels-Alder reaction of 2 and a simplified analogue of 1, namely 3, were computed at CPCM/M06-2x/6-311+G(d,p)//B3LYP/6-31G(d). The optimized transition states for the reaction of 2 and 3 are shown in Figure 1. The free energy of activation of 3 is 5.4 kcal mol-1 lower in energy than the free energy of activation of 2. This is consistent with the much faster reaction of 1 than 2 observed in the experiment.



Figure 1. B3LYP/6-31G(d) for the transition states of Reactions 2 and 3.

Partitioning 3 into fragments allows Houk and Baran to apply the distortion model. They find that the rigid diene in 3 (and thereby 1) accelerates the reaction relative to the more flexible diene of 2. Further, strain relief in going from 3 (and thereby 1) to TS3 (and thereby to TS of reaction 1) and the formation of an intramolecular hydrogen bond leads to the lower activation energy of 3, and therefore of 1.


(1) Maimone, T. J.; Voica, A.-F.; Baran, P. S. "A Concise Approach to Vinigrol," Angew. Chem. Int. Ed. 2008, 47, 3054-3056, DOI: 10.1002/anie.200800167.

(2) Diedrich, M. K.; Klärner, F.-G.; Beno, B. R.; Houk, K. N.; Senderowitz, H.; Still, W. C. "Experimental Determination of the Activation Parameters and Stereoselectivities of the Intramolecular Diels−Alder Reactions of 1,3,8-Nonatriene, 1,3,9-Decatriene, and 1,3,10-Undecatriene and Transition State Modeling with the Monte Carlo-Jumping Between Wells/Molecular Dynamics Method," J. Am. Chem. Soc. 1997, 119, 10255-10259, DOI: 10.1021/ja9643331.

(3) Krenske, E. H.; Perry, E. W.; Jerome, S. V.; Maimone, T. J.; Baran, P. S.; Houk, K. N. "Why a Proximity-Induced Diels–Alder Reaction Is So Fast," Org. Lett. 2012, 14, 3016-3019, DOI: 10.1021/ol301083q.


1: InChI=1S/C23H40O2Si/c1-10-12-19(24)21-20(16(3)4)18-13-14-23(21,15-17(18)11-2)25-26(8,9)22(5,6)7/h10-11,15-16,18-21,24H,1-2,12-14H2,3-9H3/t18?,19-,20?,21?,23+/m0/s1

2: InChI=1S/C10H16/c1-3-5-7-9-10-8-6-4-2/h3-5,7H,1-2,6,8-10H2/b7-5+

3: InChI=1S/C20H34O2Si/c1-8-10-18(21)20(15(3)4)14-17-11-12-19(20,13-16(17)9-2)22-23(5,6)7/h8-9,13,15,17-18,21H,1-2,10-12,14H2,3-7H3/t17?,18-,19+,20?/m0/s1

Diels-Alder &Houk Steven Bachrach 08 Oct 2012 2 Comments

Reaction dynamics in the Diels-Alder reaction

Has there been an organic reaction more examined by computational methods than the Diels-Alder reaction? You’d think we would have covered all aspects of this reaction by now, but no, it appears that this reaction remains fertile hunting grounds.

Doubleday and Houk have examined the Diels-Alder reaction with an eye towards its synchronicity,1 an area that Houk has delved into throughout his career. While most experiments show significant stereoselectivity, a few examples display a small amount of stereo loss. Computed transition states tend to have forming C-C bond distances that are similar, though with proper asymmetric substitution, the asymmetry of the TS can be substantial. In this paper,1 they utilize reaction dynamics specifically to assess the time differential between the formation of the two new C-C single bonds. They examined the eight reactions shown below. The first six (R1-R6) have symmetric transition states, though with the random sampling about the TS for the initial condition of the trajectories, a majority of asymmetric starting conditions are used. The last two (R7 and R8) reactions have asymmetric TSs and the random sampling amplifies this asymmetry.

Nonetheless, the results of the dynamics are striking. The time gap, the average time between the formations of the first and second new C-C bond, for R1-R6 is less than 5 fs, much shorter than a C-C vibration. These reactions must be considered as concerted and synchronous. Even the last two reactions (R7 and R8), which are inherently more asymmetric, still have very short time gaps of 15 and 56 fs, respectively. One might therefore reasonably conclude that they too are concerted and synchronous.

There are some exceptions – a few trajectories in the last two reactions involve a long-lived (~1000 fs) diradical intermediate. At very high temperature, about 2% of the trajectories invoke a diradical intermediate. But the overall message is clear: the Diels-Alder reaction is inherently concerted and synchronous.


(1) Black, K.; Liu, P.; Xu, L.; Doubleday, C.; Houk, K. N. "Dynamics, transition states, and timing of bond formation in Diels–Alder reactions," Proc. Nat. Acad. Sci. USA, 2012, 109, 12860-12865, DOI: 10.1073/pnas.1209316109

Diels-Alder &Houk Steven Bachrach 18 Sep 2012 2 Comments

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