Archive for the 'cycloadditions' Category

Bispericyclic reaction involving two [6+4] cycloadditions

Bispericyclic transition states arise when two pericyclic reactions merge to a common transition state. This leads to a potential energy surface with a bifurcation such that reactions that traverse this type of transition state will head towards two different products. The classic example is the dimerization of cyclopentadiene, involving two [4+2] Diels-Alder reactions. Unusual PESs are discussed in my book and in past blog posts.

Houk and coworkers have now identified a bispericyclic transition state involving two [6+4] cycloadditions.1 Reaching back to work Houk pursued as a graduate student with Woodward for inspiration, these authors examined the reaction of tropone 1 with dimethylfulvene 2. Each moiety can act as the diene or triene component of a [6+4] allowed cycloaddition:

The product with fulvene 2 as the 6 π-e component and tropone as the 4 π-e component [6F+4T] is 3, while reversing their participation in the [6T+4F] cycloaddition leads to 4. A variety of [4+2] reactions are also possible. All of these reactions were investigated at PCM/M06-2X/6-311+G(d,p)//B3LYP-D3/6-31G(d). The reaction leading to 3 is exothermic by 3.0 kcal mol-1, while the reaction to 4 endothermic by 1.3 kcal mol-1.

Interestingly, there is only one transition state that leads to both 3 and 4, the first known bispericyclic transition state for two conjoined [6+4] cycloadditions. The barrier is 27.9 kcal mol-1. The structures of the two products and the transition state leading to them are shown in Figure 1. 3 and 4 can interconvert through a Cope transition state, also shown in Figure 1, with a barrier of 26.3 kcal mol-1 (for 43).



TS [6+4]

TS Cope

Figure 1. B3LYP-D3/6-31G(d) optimized geometries.

Given that a single transition leads to two products, the product distribution is dependent on the molecular dynamics. A molecular dynamics simulation at B3LYP-D3/6-31G(d) with 117 trajectories indicates that 4 is formed 91% while 3 is formed only 9%. Once again, we are faced with the reality of much more complex reaction mechanisms/processes than simple models would suggest.


1) Yu, P.; Chen, T. Q.; Yang, Z.; He, C. Q.; Patel, A.; Lam, Y.-h.; Liu, C.-Y.; Houk, K. N., "Mechanisms and Origins of Periselectivity of the Ambimodal [6 + 4] Cycloadditions of Tropone to Dimethylfulvene." J. Am. Chem. Soc. 2017, 139 (24), 8251-8258, DOI: 10.1021/jacs.7b02966.


1: InChI=1S/C7H6O/c8-7-5-3-1-2-4-6-7/h1-6H

2: InChI=1S/C8H10/c1-7(2)8-5-3-4-6-8/h3-6H,1-2H3


4: InChI=1S/C15H16O/c1-9(2)14-10-7-8-11(14)13-6-4-3-5-12(10)15(13)16/h3-8,10-13H,1-2H3

cycloadditions &Dynamics &Houk Steven Bachrach 07 Aug 2017 No Comments

Dynamics in a reaction where a [6+4] and [4+2] cycloadditons compete

Enzyme SpnF is implicated in catalyzing the putative [4+2] cycloaddition taking 1 into 3. Houk, Singleton and co-workers have now examined the mechanism of this transformation in aqueous solution but without the enzyme.1 As might be expected, this mechanism is not straightforward.

Reactant 1, transition states, and products 2 and 3 were optimized at SMD(H2O)/M06-2X/def2-TZVPP//B3LYP-D3(BJ)//6-31+G(d,p). Geometries and relative energies are shown in Figure 1. The reaction 12 is a formal [6+4] cycloaddition, and the reaction 13 is a formal [4+2] cycloaddition. Interestingly, only a single transition state could be located TS1. It is a bispericyclic TS (see Chapter 4 of my book), where these two pericyclic reaction sort of merge together. After TS1 is traversed the potential energy surface bifurcates, leading to 2 or 3. This is yet again an example of a single TS leading to two different products. (See the many posts I have written on this topic.) The barrier height is 27.6 kcal mol-1, with 2 lying 13.1 kcal mol-1 above 3. However, the steepest descent pathway from TS1 leads to 2. There is a second transition state TScope that describes a Cope rearrangement between 2 and 3. Using the more traditional TS theory description, 1 undergoes a [6+4] cycloaddition to form 2 which then crosses a lower barrier (TScope) to form the thermodynamically favored 3, which is the product observed in the enzymatically catalyzed reaction.

1 (0.0)

TS1 (27.6)

2 (4.0)

3 (-9.1)


Figure 1. B3LYP-D3(BJ)//6-31+G(d,p) optimized geometries and relative energies in kcal mol-1.

Molecular dynamics computations were performed on this system by tracking trajectories starting in the neighborhood of TS1 on a B3LYP-D2/6-31G(d) PES. The results are that 63% of the trajectories end at 2, 25% end at 3, and 12% recross back to reactant 1, suggesting an initial formation ratio for 2:3 of 2.5:1. The reactions are very slow to cross through the “transition zone”, typically 2-3 times longer than for a usual Diels-Alder reaction (see this post).

Once again, we see an example of dynamic effects dictating a reaction mechanism. The authors pose a tantalizing question: Can an enzyme control the outcome of an ambimodal reaction by altering the energy surface such that the steepest downhill path from the transition state leads to the “desired” product(s)? The answer to this question awaits further study.


(1) Patel, A; Chen, Z. Yang, Z; Gutierrez, O.; Liu, H.-W.; Houk, K. N.; Singleton, D. A. “Dynamically
Complex [6+4] and [4+2] Cycloadditions in the Biosynthesis of Spinosyn A,” J. Amer. Chem. Soc. 2016, 138, 3631-3634, DOI: 10.1021/jacs.6b00017.


1: InChI=1S/C24H34O5/c1-3-21-15-12-17-23(27)19(2)22(26)16-10-7-9-14-20(25)13-8-5-4-6-11-18-24(28)29-21/h4-11,16,18-21,23,25,27H,3,12-15,17H2,1-2H3/b6-4+,8-5+,9-7+,16-10+,18-11+/t19-,20+,21-,23-/m0/s1

2: InChI=1S/C24H34O5/c1-3-19-8-6-10-22(26)15(2)23(27)20-12-11-17-14-18(25)13-16(17)7-4-5-9-21(20)24(28)29-19/h4-5,7,9,11-12,15-22,25-26H,3,6,8,10,13-14H2,1-2H3/b7-4-,9-5+,12-11+/t15-,16-,17-,18-,19+,20+,21-,22+/m1/s1

3: InChI=1S/C24H34O5/c1-3-19-5-4-6-22(26)15(2)23(27)11-10-20-16(9-12-24(28)29-19)7-8-17-13-18(25)14-21(17)20/h7-12,15-22,25-26H,3-6,13-14H2,1-2H3/b11-10+,12-9+/t15-,16+,17-,18-,19+,20-,21-,22+/m1/s1

cycloadditions &Diels-Alder &Dynamics &Houk &Singleton Steven Bachrach 30 Aug 2016 1 Comment

Cyclization reaction of 1,2-cyclohexadiene

1,2-Cyclohexadiene 1 is a very strained and highly reactive species. Houk, Garg and co-workers report on its use as the ene component in a cyclization with a 1,3-dipole, namely nitrones.1 For example, 1 reacts with nitrone 2 to give the cycloadducts 3a and 3b in a ratio of 8.9:1.

To investigate the mechanism of this reaction, they optimized the structures of all compounds at CPCM(acetonitrile)B3LYP/6-31G(d) and single-point energies were obtained using the B3LYP-D3 functional. The structures of some pertinent critical points are shown in Figure 1. They did locate a concerted transition state (TS1) leading to 3a, with a barrier of 14.5 kcal mol-1, but could not find a concerted TS leading to 3b. (Also, the barriers leading to the other regioisomer are much higher than the ones leading to the observed products.) Rather, they identified a stepwise transition state (TS2) with a barrier of nearly the same energy (14.4 kcal mol-1) that leads to the intermediate (INT), which lies 16.5 kcal mol-1 below reactants. They located two transition states from his intermediate, TS3a and TS3b, leading to the two different products. The barrier to 3a is 1.2 kcal mol-1 lower than the barrier leading to 3b, and this corresponds nicely with the observed diastereoselectivity.









Figure 1. CPCM(acetonitrile)B3LYP/6-31G(d) optimized geometries and CPCM(acetonitrile)B3LYP-D3/6-31G(d) free energies.


(1) Barber, J. S.; Styduhar, E. D.; Pham, H. V.; McMahon, T. C.; Houk, K. N.; Garg, N. K.
"Nitrone Cycloadditions of 1,2-Cyclohexadiene," J. Am. Chem. Soc. 2016, 138, 2512-2515, DOI: 10.1021/jacs.5b13304.


1: InChI=1S/C6H8/c1-2-4-6-5-3-1/h1,5H,2,4,6H2

2: InChI=1S/C11H15NO/c1-11(2,3)12(13)9-10-7-5-4-6-8-10/h4-9H,1-3H3/b12-9-

3a: InChI=1S/C17H23NO/c1-17(2,3)18-16(13-9-5-4-6-10-13)14-11-7-8-12-15(14)19-18/h4-6,9-11,15-16H,7-8,12H2,1-3H3/t15-,16-/m0/s1

3b: InChI=1S/C17H23NO/c1-17(2,3)18-16(13-9-5-4-6-10-13)14-11-7-8-12-15(14)19-18/h4-6,9-11,15-16H,7-8,12H2,1-3H3/t15-,16+/m1/s1

cycloadditions &Houk Steven Bachrach 11 Apr 2016 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

Benzene Dimers – [2+2] and [4+2]

Hoffmann1 reports on a number of new benzene dimer structures, notably 5-8, whose RIJCOSX-MP2/cc-pVTZ2 structures are shown in Figure 1. A few of these new dimers are only somewhat higher in energy than the known dimers 1-4. The energies of these dimers, relative to two isolated benzene molecules, are listed in Table 1.









Figure 1. RIJCOSX-MP2/cc-pVTZ optimized geometries of 1-8.

Table 1. Energy (kcal mol-1) of the dimers relative to two benzene molecules and activation energy for reversion to two benzene molecules.




























The energy for reversion of the isomers 5-8 to two isolated benzene molecules is calculated to be fairly large, and so they should be stable relative to that decomposition mode. They also examined a series of other decomposition modes, including [1,5]-hydrogen migration, all of which had barriers of 21 kcal mol-1 or greater, retrocyclization ([2+2]), for which they could not locate transition states, electrocyclic ring opening (Cope), with barriers of at least 17 kcal mol-1 and dimerization – some of which had relatively small enthalpic barriers of 4-5 kcal mol-1. However, the dimerizations all have very unfavorable entropic activation barriers.

So, the conclusion is that all of the novel dimers (48) can be reasonable expected to hang around for some time and therefore are potential synthetic targets.


(1) Rogachev, A. Yu.; Wen, X.-D.; Hoffmann, R. "Jailbreaking Benzene Dimers," J.
Am. Chem. Soc.
, 2012, 134, 8062-8065, DOI:10.1021/ja302597r

(2) Kossmann, S.; Neese, F. "Efficient Structure Optimization with Second-Order Many-Body Perturbation Theory: The RIJCOSX-MP2 Method," J. Chem. Theory Comput., 2010, 6, 2325-2338, DOI: 10.1021/ct100199k


1: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10+,11-,12+

2: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10+,11+,12-

3: InChI=1S/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H/t9?,10?,11-,12+

4: InChI=1S/C12H12/c1-2-10-4-3-9(1)11-5-7-12(10)8-6-11/h1-12H

5: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11+,12+/m1/s1

6: InChI=1S/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H/t9?,10?,11-,12-/m0/s1

7: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11-,12+/m1/s1

8: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11-,12-

Aromaticity &cycloadditions &electrocyclization Steven Bachrach 04 Jun 2012 No Comments

More strange dynamics from the Singleton Group

Once again the Singleton group reports experiments and computations that require serious reconsideration of our notions of reaction mechanisms.1 In this paper they examine the reaction of dichloroketene with labeled cis-2-butene. With 13C at the 2 position of 2-butene, two products are observed, 1 and 1’, in a ratio of 1’:1 = 0.993 ± 0.001. This is the opposite what one might have imagined based on the carbonyl carbon acting as an electrophile.

The first interesting item is that B3LYP/6-31+G** fails to predict the proper structure of the transition state. It predicts an asymmetric structure 2, shown in Figure 1, while MPW1k/6-31+G**, M06, and MP2 predict a Cs transition structure 3. The Cs TS is confirmed by a grid search of M06-2x geometries with CCSD(T)/6-311++G88/PCM(CH2Cl2) energies.



Figure 1. Optimized TSs 2 (B3LYP/6-31+G**) and 3 (MPW1K/6-31+G**).

The PES using proper computational methods is bifurcating past TS 3, falling downhill to product 1 or 1’. Lying on the Cs plane is a second transition state that interconverts 1 and 1’. On such a surface, conventional transition state theory would predict equal amounts of 1 and 1’, i.e. no isotope effect! So they must resort to a trajectory study – which would be impossibly long if not for the trick of making the labeled carbon super-heavy – like 28C,44C, 76C and 140C and then extrapolating back to just ordinary 13C. These trajectories indicate a ratio of 1’:1 of 0.990 in excellent agreement with the experimental value of 0.993.

Interestingly, most trajectories recross the TS, usually by reaching into the region near the second TS. However, the recrossing decreases with increasing isotopic mass, and this leads to the isotope effect. It turns out the vibrational mode 3 breaks the Cs symmetry; movement in one direction along mode 3 has no mass dependence but in the opposite direction, increased mass leads to decreased recrossing – or put in another way, in this direction, increased mass leads more often to product.

But one can understand this reaction from a statistical point of view as well. If one looks at the free energy surface, there is a variational TS near 3, but then there is a second set of variational transition states (one leading to 1 and one to 1’) which are associated with the formation of the second C-C bond. In a sense there is an intermediate past 3 that leads to two entropic barriers, one on a path to 1 and one on the path to 1’. RRKM using this model gives a ratio of 0.992 – again in agreement with experiment! It is as Singleton notes “perplexing”; how do you reconcile the statistical view with the dynamical (trajectory) view? Singleton has no full explanation.

Lastly, they point out that a similar situation occurs in the organocatalyzed Diels-Alder reaction of MacMillan shown below.2 (This reaction is also discussed in a previous post.) Now Singleton finds that the “substituent effects, selectivity, solvent effects, isotope effects and activation parameters” are all dictated by a second variational TS far removed from the conventional electronic TS.


(1) Gonzalez-James, O. M.; Kwan, E. E.; Singleton, D. A., "Entropic Intermediates and Hidden Rate-Limiting Steps in Seemingly Concerted Cycloadditions. Observation, Prediction, and Origin of an Isotope Effect on Recrossing," J. Am. Chem. Soc. 2012, 134, 1914-1917, DOI: 10.1021/ja208779k

(2) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C., "New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic Diels-Alder Reaction," J. Am. Chem. Soc. 2000, 122, 4243-4244, DOI: 10.1021/ja000092s.


2-butene: InChI=1/C4H8/c1-3-4-2/h3-4H,1-2H3/b4-3-

Dichloroketene: InChI=1/C2Cl2O/c3-2(4)1-5

1 (no isotope): InChI=1/C6H8Cl2O/c1-3-4(2)6(7,8)5(3)9/h3-4H,1-2H3/t3-,4+/m0/s1

cycloadditions &Dynamics &Isotope Effects &Singleton Steven Bachrach 06 Mar 2012 2 Comments

trans-Cyclooctene as a Click Alternative

The click reaction, the copper-assisted cycloaddition of an azide with an alkyne, has been extended to biological systems by use of a strained alkyne (cyclooctyne) thereby eliminating the need of the toxic copper agent.1 Fox has extended this analogy with the reaction of strained trans-cyclooctene 1 with tetrazine 2.2

The interesting new twist here is to add more strain to trans-cyclooctene to perhaps make the cycloaddition even faster. Bach3 had pointed out that the half chair conformation of 1 is almost 6 kcal mol-1 higher in energy than the ground state (Figure 1). Fox suggests that fusing a cyclopropyl ring to the eight-member ring would create a ring in the half chair 3. Since 3 would be even more strained than 1, it should undergo a faster cycloaddition reaction.


1 (half chair)


Figure 1. M06L/6-311+G(d,p) optimized structures of 1 and 3.

Though Fox did not estimate the strain of 3, I have computed the structure of 1 constrained to the geometry of 3, with the two hydrogens that replace the bonds to the cyclopropyl carbon allowed to optimize. This restricted geometry is in fact 6.1 kcal mol-1 (M06L/6-311+G(d,p)) higher in energy than 1 – so the fusion of the 3-member ring does net the strain increase expected by Bach.

Fox reports estimates of the free energy of activation (at M06L/6-311+G(d,p)) for the reaction of 1or 3 with 2. The barrier for the raction with trans-cyclooctene 1 is 8.92 kcal mol-1, while the barrier for the reaction with 3 is 6.95 kcal mol-1. A methylenehydroxyl derivative of 3 was synthesized and it does react 180 times faster than the reaction with 1. Furthermore, the differences in the experimental free energies of activation is 3.0 kcal mol-1, in excellent agreement with the computed difference.


(1) Agard, N. J.; Prescher, J. A.; Bertozzi, C. R., "A Strain-Promoted [3 + 2] Azide-Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems," J. Am. Chem. Soc., 2004, 126, 15046-15047, DOI: 10.1021/ja044996f

(2) Taylor, M. T.; Blackman, M. L.; Dmitrenko, O.; Fox, J. M., "Design and Synthesis of Highly Reactive Dienophiles for the Tetrazine-trans-Cyclooctene Ligation," J. Am. Chem. Soc., 2011, 133, 9646-9649, DOI: 10.1021/ja201844c

(3) Bach, R. D., "Ring Strain Energy in the Cyclooctyl System. The Effect of Strain Energy on [3 + 2] Cycloaddition Reactions with Azides," J. Am. Chem. Soc., 2009, 131, 5233-5243, DOI: 10.1021/ja8094137


1: InChI=1/C8H14/c1-2-4-6-8-7-5-3-1/h1-2H<,3-8H2/b2-1+

2: InChI=1/C12H8N6/c1-3-7-13-9(5-1)11-15-17-12(18-16-11)10-6-2-4-8-14-10/h1-8H

3: InChI=1/C9H14/c1-2-4-6-9-7-8(9)5-3-1/h1-2,8-9H,3-7H2/b2-1+/t8-,9+

cycloadditions Steven Bachrach 07 Sep 2011 No Comments

[8+2] cycloaddition is stepwise

While many pericyclic reactions proceed in a concerted fashion, the stepwise pathway is a distinct possibility. Fernandez, Sierra and Torres report on an interesting [8+2] cycloaddition that
is decidedly stepwise, confirmed through trapping of the intermediate zwitterion.1

The reaction of 1 with 2 was examined at M06-2x/6-311+G(d) (optimized geometries of the critical points are shown in Figure 1). The first transition state (TS1) has nitrogen acting as a nucleophile, attacking the carbonyl carbon of ketene to give 3. The barrier is 11.6 kcal mol-1, and 3 lies 0.7 kcal mol-1 above reactants. While 3 might be described with a tropyllium cation resonance structure, the ring is in fact non-planar and both the NICS(0) and NICS(1)zz values are positive. The ring is therefore antiaromatic, consistent with the endoergonicity of this step. Closure of the zwitterion through TS2 leads to the formal [8+2] product, with the barrier for this second step slightly lower than the barrier for the first step. Overall, the reaction is quite exothermic.

Scheme 1 (relative energies in kcal mol-1)





Figure 1. MO6-2x/6-311+G(d) optimized Structures of 3, 4, and the transition states leading to them (TS1 and TS2).

Experiments were performed with a variety of acyl chloride precursors to ketenes (Scheme 2), and along with the [8+2] product, a second product (5) incorporating 2 equivalents of ketene is found; in fact, if the R group is benzyloxy or t-butyl, 5 is the only observed product. This second product comes about via trapping of the intermediate 3. Mixing phenylketene with 4a (where the R group is phenyl) gives no reaction, thus precluding the intermediacy of 4 on the path to 5. MO6-2x computations of the trapping of 3 with phenylketenes indicates a barrier (TS3, see Figure 2) of 9.6 kcal mol-1, very close to the barrier height of the second TS for ring closure of the [8+2] pathway, supporting the competition between trapping of the intermediate and progress on to the [8+2] product.

Scheme 2.


Figure 2. MO6-2x/6-311+G(d) optimized Structures of TS3.


(1) Lage, M. L.; Fernandez, I.; Sierra, M. A.; Torres, M. R., "Trapping Intermediates in an [8 + 2] Cycloaddition Reaction with the Help of DFT Calculations," Org. Lett., 2011, ASAP, DOI: 10.1021/ol200910z


1: InChI=1/C8H6O/c9-7-6-8-4-2-1-3-5-8/h1-6H

2: InChI=1/C7H7N/c8-7-5-3-1-2-4-6-7/h1-6,8H

3: InChI=1/C15H13NO/c17-15(12-13-8-4-3-5-9-13)16-14-10-6-1-2-7-11-14/h1-12,17H/b15-12-/f/h17h,16H

4: InChI=1/C15H13NO/c17-15-14(11-7-3-1-4-8-11)12-9-5-2-6-10-13(12)16-15/h1-10,12,14H,(H,16,17)/t12-,14+/m1/s1/f/h16H

cycloadditions Steven Bachrach 05 Jul 2011 2 Comments

[6+4] and [4+2] cycloadditions: Unusual potential energy surfaces

Alder and co-workers have published a substantial theoretical study of potential [6+4]-cycloaddition reactions.1 There is much too much to summarize from this study, but I highlight here an interesting result that is consistent with one of the themes of the book and blog: unusual potential energy surfaces.

They examined two [6+4]-cycloadditon routes involving 1,3,5-hexatriene with 1,3-butadiene to give 1 and 2. These products are shown in Figure 1. A competing [4+2]-cycloaddition is also possible, giving rise to 3 and 4. Interestingly, only one TS is found leading to 1/3 and one TS leading to 2/4. (These TSs are also shown in Figure 1.) This is reminiscent of many examples from the book and blog where a single TS seems to lead to 2 different products. A valley-ridge inflection point divides the surface between 1 and 3 (VRI-1), and a second valley-ridge inflection point separates 2 from 4 (VRI-2). In addition a Cope transition state (CTS1) takes 1 into 3, and a second TS (CTS2) takes 2 into 4.







Figure 1. B3LYP/6-31G* optimized structures of the TSs and products of the reaction of 1,3,5-hexadiene with 1,3-butadiene.1

This type of surface requires study of the dynamics to truly predict what the outcome will be of the reaction. Unfortunately, the low barriers for the Cope rearrangements along with 3 and 4 being much more stable than 1 and 2 indicates that the [6+4] product is unlikely to be observed. Nonetheless, this is yet another example of an unexpected PES.


(1) Alder, R. W.; Harvey, J. N.; Lloyd-Jones, G. C.; Oliva, J. M., "Can π6 + π4 = 10? Exploring Cycloaddition Routes to Highly Unsaturated 10-Membered Rings," J. Am. Chem. Soc. 2010, 132, 8325-8337, DOI: 10.1021/ja1008135


1: InChI=1/C10H14/c1-2-4-6-8-10-9-7-5-3-1/h1-4,9-10H,5-8H2/b3-1-,4-2+,10-9+

2: InChI=1/C10H14/c1-2-4-6-8-10-9-7-5-3-1/h1-4,9-10H,5-8H2/b3-1-,4-2-,10-9+

3: InChI=1/C10H14/c1-3-9-7-5-6-8-10(9)4-2/h3-5,7,9-10H,1-2,6,8H2/t9-,10-/m0/s1

4: InChI=1/C10H14/c1-3-9-7-5-6-8-10(9)4-2/h3-5,7,9-10H,1-2,6,8H2/t9-,10+/m1/s1

cycloadditions &Dynamics Steven Bachrach 20 Jul 2010 1 Comment

Racemization of imidazolines

Grinberg and colleagues have published a combination of VCD and computation to understand the racemization of imidazoline 1 when exposed to base.1 Experimental VCD performed at various temperatures indicates first-order kinetics with a barrier of about 24 kcal mol-1.

The mechanism for this racemization was proposed and supported with B3LYP/6-31G(d) computations. The anion of 1 can undergo a disrotatory ring opening to form 2, passing through TS1 with a barrier of about 21 kcal mol-1. Since 2 is chiral with the phenyl groups oriented in non-equivalent positions, ring closure of 2 will go back to 1 and not on to its racemate. In order to racemize, 2 must convert to 3, which can invert to 3’ and then on to 1’. While the barrier for ring opening is likely to be rate limiting, and it does match up reasonably well with the experimental value, the authors have not optimized the transition state that take 2 into 3 or the TS that interconverts 3 with 3’. It’s the former TS that may be pretty large as it requires disruption of the conjugation. Unfortunately, not only have the authors not computed these other TSs, the supplementary materials include only the optimized structure of 1 and not TS1, 2, or 3!

The authors do note that the ring opening is facilitated by the phenyl group on the chiral carbons of 1. They replaced the phenyls with cyclohexyl or cyclohexenyl groups and racemization is no longer observed. Strangely, the authors include in the supporting materials the optimized structures of these variants, but not the TSs for ring opening. Thus, the confirming evidence of a very high barrier for ring opening that would really nail down the mechanism is missing!


1) Ma, S.; Busacca, C. A.; Fandrick, K. R.; Bartholomeyzik, T.; Haddad, N.; Shen, S.; Lee, H.; Saha, A.; Yee, N.; Senanayake, C.; Grinberg, N., "Directly Probing the Racemization of Imidazolines by Vibrational Circular Dichroism: Kinetics and Mechanism," Org. Lett., 2010, 12, 2782–2785, DOI: 10.1021/ol100734t


1: InChI=1/C21H18N2/c1-4-10-16(11-5-1)19-20(17-12-6-2-7-13-17)23-21(22-19)18-14-8-3-9-15-18/h1-15,19-20H,(H,22,23)/t19-,20-/m0/s1/f/h22H

cycloadditions Steven Bachrach 13 Jul 2010 No Comments

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