Archive for the 'Dynamics' Category

Dynamic effects in nucleophilic substitution

I think most organic chemists hold dear to their hearts the notion that selectivity is due to crossing over different transition states. Readers of my book and this blog know of the many examples where this notion simply is not true (see here). This post discusses yet another example taking place in a seemingly simple reaction.

Singleton has examined the nucleophilic substitution reaction of 1 with sodium tolylsulfide.1 The mono substitution gives potentially two different stereoproducts 2 and 3. The experimental ratio of these products 2:3 is 81:19. (Note that things are a bit more complicated because disubstitution can also occur, but this has been factored into the product ratio.)

Based on previous literature, this reaction is likely to proceed in a concerted fashion, and so one might anticipate running computations to locate a transition state leading to 2 and a transition state leading to 3. In fact, Singleton finds six different TSs (the lowest energy TS 4 is shown in Figure 1), all within 2 kcal mol-1 of each other at PCM(ethanol)/B3LYP/6-31+G**. However, the intrinsic reaction coordinate going forward from each of these six TSs leads solely to 2; no TS could be located that connects to 3! (Computations were also performed at PCM(ethanol)/M06-2x/6-31+G** which give very similar results.) Classical transition state theory would lead
one to conclude that only 2 should be formed, inconsistent with experiment.



Figure 1. PCM/B3LYP/6-31+G** optimized structures of TSs 4 and 5.

Furthermore, no intermediate could be located. This is consistent with a concerted mechanism. A second transition state was located which interconverts 2 and 3 with the involvement of a chloride – a sort of addition/rotation/elimination process. This TS 5 is also shown in Figure 1.

A direct dynamics study was performed, and 197 trajectories were computed. Of these, 185 trajectories went to product: 156 to 2 and 29 to 3, for a ratio of 84:16 – in amazing agreement with experiment! The product selectivity is due entirely to dynamic effects. In fact, it is one vibrational mode that dictates the product distribution. Essentially, the nature of the rotation about the C=C bond differentiates the eventual route, with a clockwise rotation leading always to 2 and a counterclockwise rotation leading about a third of the time to 3.


(1) Bogle, X. S.; Singleton, D. A. "Dynamic Origin of the Stereoselectivity of a Nucleophilic Substitution Reaction," Org. Lett., 2012, 14, 2528-2531, DOI: 10.1021/ol300817a.


1: InChI=1S/C4H4Cl2O/c1-3(7)2-4(5)6/h2H,1H3

2: InChI=1S/C11H11ClOS/c1-8-3-5-10(6-4-8)14-11(12)7-9(2)13/h3-7H,1-2H3/b11-7-

3: InChI=1S/C11H11ClOS/c1-8-3-5-10(6-4-8)14-11(12)7-9(2)13/h3-7H,1-2H3/b11-7+

Dynamics &Singleton &Substitution Steven Bachrach 03 Jul 2012 12 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

Roaming mechanism in photodissociation of nitrobenzene

The roaming mechanism has gained some traction as a recognizable model.1,2 This mechanism involves typically the near complete dissociation of a molecule into two radical fragments. But before they can completely separate they form a loose complex on a flat potential energy surface. The two fragments can then wander about each other (the “roaming” part of the mechanism), eventually finding an alternative exit channel. The first example was the dissociation of formaldehyde which forms the complex H + CHO.3 The hydrogen atom roams over to the other side of the HCO fragment and then abstracts the second hydrogen atom to form H2 and CO – with the unusual signature of a hot H2 molecule and CO in low rotational/vibrational states.

The photodissociation of nitrobenzene is now suggested to also follow a roaming pathway.4 Bimodal distribution is found for the NO product channel. There is a slow component with low J and a fast component with high J. This suggests two different operating mechanisms for dissociation.

G2M(CC1)/UB3LYP/6-311+G(3df,2p) computations provide the two mechanisms. Near dissociation to phenyl radical and NO2 can lead to a roaming process that eventually leads to recombination to form phenyl nitrite, which can then dissociate to the slow NO product. The fast NO product is suggested to come from rearrangement of nitrobenzene to phenylnitrite on the triplet surface, again eventually leading to loss of NO, but with high rotational excitation.


(1) Herath, N.; Suits, A. G., "Roaming Radical Reactions," J. Phys. Chem. Lett. 2011, 2, 642-647, DOI: 10.1021/jz101731q

(2) Bowman, J. M.; Suits, A. G., "Roaming reactions: The third way," Phys. Today 2011, 64, 33-37, DOI: 10.1063/PT.3.1330

(3) Townsend, D.; Lahankar, S. A.; Lee, S. K.; Chambreau, S. D.; Suits, A. G.; Zhang, X.; Rheinecker, J.; Harding, L. B.; Bowman, J. M., "The Roaming Atom: Straying from the Reaction Path in Formaldehyde Decomposition," Science 2004, 306, 1158-1161, DOI: 10.1126/science.1104386.

(4) Hause, M. L.; Herath, N.; Zhu, R.; Lin, M. C.; Suits, A. G., "Roaming-mediated isomerization in the photodissociation of nitrobenzene," Nat. Chem 2011, 3, 932-937, DOI: 10.1038/nchem.1194


Nitrobenzene: InChI=1/C6H5NO2/c8-7(9)6-4-2-1-3-5-6/h1-5H

Dynamics Steven Bachrach 21 Feb 2012 No Comments

Nonstatistical dynamics in [1,5]-hydrogen migration

The [1,5]-H migration in cyclopentadiene seems like it should be a very ordinary reaction. A molecular dynamics study by Carpenter at first glance appears to confirm this notion.1 Trajectories studies show that the ratio of endo:exo migration is very close to 1:1, suggesting, as expected, statistical behavior. However, inspection of the time dependence of the endo to exo migration shows oscillatory behavior. This oscillation corresponds to the B1 vibration that effectively flips the methylene group through the ring plane and interchanges the exo and endo hydrogens. The hydrogen preferentially migrates from the endo position, with the ring bent by typically 10°, a point far from the computed [1,5]-H migration transition state (which is planar).

Differential damping this B1 vibration should then lead to variable endo:exo ratios, and Carpenter suggests that performing this reaction in the gas phase and in solution with different solvent viscosities should exhibit such a variable ratio. The experiment awaits an experimenter!

Once again the take-home message is that dynamics matter, even in seemingly simple and well-understood processes. Reactions can take place far from the nominal transition state and the consequences can be significant.


(1) Goldman, L. M.; Glowacki, D. R.; Carpenter, B. K., "Nonstatistical Dynamics in Unlikely Places: [1,5] Hydrogen Migration in Chemically Activated Cyclopentadiene," J. Am. Chem. Soc. 2011, 133, 5312-5318, DOI: 10.1021/ja1095717

Dynamics Steven Bachrach 24 Jan 2012 1 Comment

Substitution vs. addition: dynamic effects

Reactions whose outcomes depend on dynamic processes is a major theme of my book and this blog. The recent study of the reaction of a nucleophile (hydroxide) with bromoacetophenones adds yet another case for post-transition state product determination.

Itoh and Yamataka have examined the reaction of hydroxide with substitutes α-bromoacetophenones 1.1 The nucleophile can attack at the carbonyl carbon or the α-carbon, though both lead ultimately to the same product, as shown in Scheme 1.

Scheme 1

B3LYP/6-31+G* computations of the reaction surface with a variety of different substituents on the phenyl ring of 1 located in all cases a single transition state for the two different reactions (addition and substitution). This TS is shown in Figure 1 for the parent case (X=H).

Figure 1. The single transition state for the addition and substitution reaction of 1 and hydroxide.

Tracing the IRC forward leads to either the carbonyl addition product or the substitution product, and which path is traced depends to some extent on the nature of the substituent. Most intriguing is that trajectories initiated at the transition state lead to both products. So once again, we see a case where a single transition state leads to two products, and product selectivity is determine by the dynamics – the initial conditions at the TS dictate which of the two products is eventually obtained.


(1) Itoh, S.; Yoshimura, N.; Sato, M.; Yamataka, H., "Computational Study on the Reaction Pathway of α-Bromoacetophenones with Hydroxide Ion: Possible Path Bifurcation in the Addition/Substitution Mechanism," J. Org. Chem., 2011, 70, 8294–8299, DOI: 10.1021/jo201485y

Dynamics &Substitution Steven Bachrach 24 Oct 2011 13 Comments

Hydroboration revisited – and more complicated!

In a previous post, I described the work of Singleton on a simple hydroboration reaction. He found less regioselectivity than predicted by transition state theory. Further, trajectory computations suggested that dynamic effects were at play, and that some non-selective fast reactions were leading to the lower regioselection.

Pilling offers an alternative explanation based solely on RRKM (statistical) theory.1 (Actually what is utilized is the stochastic energy grained master equation.) What he suggests is that there are hot intermediates (formed of a loose associate of BH3 with propene) that react non-selectively before cooling. The cooled intermediates react very selectively (around 99%) to give the anti-Markovnikov product.

The upshot is that hydroboration – and by implication a whole lot of other seemingly ordinary chemistry – may in fact be much more complicated than we had previously thought. Standard transition state theory may not always apply, and trajectory analysis may not be enough!


(1) Glowacki, D. R.; Liang, C. H.; Marsden, S. P.; Harvey, J. N.; Pilling, M. J., "Alkene Hydroboration: Hot Intermediates That React While They Are Cooling," J. Am. Chem. Soc., 2010, 132, 13621-13623, DOI: 10.1021/ja105100f

Dynamics Steven Bachrach 30 Nov 2010 No 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

More dynamic effects in Diels-Alder reactions

Dynamic effects rear up yet again in a seemingly simple reaction. Singleton has examined the Diels-Alder cycloaddition of acrolein with methyl vinyl ketone to give two cross products 1 and 2.1 Upon heating the product mixture, 1 is essentially the only observed species. The retro-Diels-Alder is much slower than the conversion of 2 into 1. Using a variety of rate data, the best estimate for the relative formation of 1:2 is 2.5.

The eight possible transition states for this reaction were computed with a variety of methodologies, all providing very similar results. The lowest energy TS is TS3. A TS of type TS4 could not be found; all attempts to optimize it collapsed to TS3.

IRC computations indicate the TS3 leads to 1. The lowest energy TS that leads to 2 is TS6, but a second TS (TS5) lower in energy than TS6 also leads to 1. The other TS are still higher in energy. A Cope-type TS that interconverts 1 and 2 (TS7) was also located. The geometries of these TSs are shown in Figure 1.





Figure 1. MP2/6-311+G** optimized geometries and relative energies (kcal mol-1) of TS3-TS7.1

Ordinary transition state theory cannot explain the experimental results – the energy difference between the lowest barrier to 1 (TS3) and to 2 (TS6) suggests a rate preference of over 700:1 for 1:2. But the shape of the potential energy surface is reminiscent of others that have been discussed in both my book (Chapter 7) and this blog (see my posts on dynamics) – a surface where trajectories cross a single TS but then bifurcate into two product wells.

To address the chemical selectivity on a surface like this, one must resort to molecular dynamics and examine trajectories. In their MD study of the 296 trajectories that begin at TS3 with motion towards product, 89 end at 1 and 33 end at 2, an amazingly good reproduction of experimental results! Interestingly, 174 trajectories recross the transition state and head back towards reactants. These recrossing trajectories result from “bouncing off” the potential energy wall of the forming C4-C5 bond.

In previous work, selectivity in on these types of surfaces was argued in terms of which well the TS was closer to. But analysis of the trajectories in this case revealed that a strong correlation exists between the initial direction and velocity in the 98 cm-1 vibration – the vibration that corresponds to the closing of the second σ bond, the one between C6-O1 (forming 1), in the negative direction, and closing the C­3-O8 bond (forming 2) in the positive direction. Singleton argues that this is a type of dynamic matching, and it might be more prevalent that previously recognized.


(1) Wang, Z.; Hirschi, J. S.; Singleton, D. A., "Recrossing and Dynamic Matching Effects on Selectivity in a Diels-Alder Reaction," Angew. Chem. Int. Ed., 2009, 48, 9156-9159, DOI: 10.1002/anie.200903293


1: InChI=1/C7H10O2/c1-6(8)7-4-2-3-5-9-7/h3,5,7H,2,4H2,1H3

2: InChI=1/C7H10O2/c1-6-3-2-4-7(5-8)9-6/h3,5,7H,2,4H2,1H3

Diels-Alder &Dynamics &Singleton Steven Bachrach 27 Apr 2010 No Comments

Dynamics in 1,3-dipolar cycloadditions (2)

Houk and Doubleday have a nice follow-up study1 to their previous MD study2 of 1,3-dipolar cycloadditions, which I posted on here. They report on the cycloaddition of either acetylene or ethylene to 9 different 1,3-dipoles. Continuing on Houk’s recent thread of looking at distortion energies to attain the TS, they note that a sizable fraction (often over 50%) of the distortion energy is associated with bending the X-Y-Z bond of the dipole, consistent with their earlier work suggesting the importance of this vibration in attaining and crossing the TS. What’s new in this paper is the extensive MD studies, with trajectory studies of all 18 reactions. These revealed again the importance of vibrational energy in this X-Y-Z bending mode in crossing the TS. They also noted the role of translational energy, and the relationship between translational vs. vibrational energy depending on the early/late nature of the TS. Their final point was that the lifetime of any diradical or diradical-like intermediate is so short, less than the time of a bond vibration, so that one can discount any diradical participation. The reaction is concerted.


(1) Xu, L.; Doubleday, C. E.; Houk, K. N., "Dynamics of 1,3-Dipolar Cycloadditions: Energy Partitioning of Reactants and Quantitation of Synchronicity," J. Am. Chem. Soc., 2010, ASAP, DOI: /10.1021/ja909372f

(2) Xu, L.; Doubleday, C. E.; Houk, K. N., "Dynamics of 1,3-Dipolar Cycloaddition Reactions of Diazonium Betaines to Acetylene and Ethylene: Bending Vibrations Facilitate Reaction," Angew. Chem. Int. Ed., 2009, 48, 2746-2748, DOI: 10.1002/anie.200805906

Dynamics &Houk Steven Bachrach 21 Apr 2010 1 Comment

Cycloadditions of cyclodienes with ketenes

One more study of cyclodiene reactions with ketenes that suggest the occurrence of dynamic effects.1 The reaction of cyclopentadiene with t-butylcyanoketene 1 gives cyclobutanone 2 solely. In contrast, the reaction of 1,3-cyclophexadiene with 1 gives the cyclobutanone 3 and a small amount (less than 25%) of the ether 4. Warming the reaction from -20 °C to 20 °C leads to loss of 3 and an increase in 4. This is in distinct contrast with the reaction of cyclopentadiene with diphenylketene,2 where the ether product is the major product and the cyclobutenone is the minor product (see Chapter in my book).

To help understand this situation, the authors optimized the structures of the critical points on the surface of the cyclohexadiene reaction at MPWB1K/6-31+G(d,p) – though once again, there are no supporting materials so I cannot supply the 3-D structures in the blog! 4 is predicted to be 3.4 kcal mol-1 more stable than 3, which accounts for it being the thermodynamic product, consistent with experiment. Only two transition states are found. The first TS, with a barrier of 23.2 kcal mol-1, connects reactants with 3. The second transition state corresponds to the oxy-Cope rearrangement that takes 3 into 4. This surface is reminiscent of many others that display dynamic effects (again see my book and also these posts). Unfortunately, the authors have not performed any trajectory calculation. But one might expect that most trajectories cross the first transition state and fall into the well associated with 3. Some of these molecules then go on to cross the second barrier to form 4. But some trajectories cross the first TS and then veer off into the slightly lower well associated with 4, being directly formed from reactant. This would be a manifestation of dynamic effects, and is worth further study.


(1) Marton, A.; Pârvulescu, L.; Draghici, C.; Varga, R. A.; Gheorghiu, M. D., "Reaction of Moore’s ketene (tert-butylcyanoketene) with 1,3-cyclopentadiene and 1,3-cyclohexadiene. Is periselectivity controlled by the dynamic of trajectories at the bifurcation point?," Tetrahedron, 2009, 65, 7504-7509, DOI: 10.1016/j.tet.2009.07.020.

(2) Ussing, B. R.; Hang, C.; Singleton, D. A., "Dynamic Effects on the Periselectivity, Rate, Isotope Effects, and Mechanism of Cycloadditions of Ketenes with Cyclopentadiene," J. Am. Chem. Soc., 2006, 128, 7594-7607, DOI: 10.1021/ja0606024.

Dynamics Steven Bachrach 06 Apr 2010 No Comments

Next Page »