Reaction Mechanism « Henry Rzepa's blog

Posts Tagged ‘Reaction Mechanism’

The π-complex in the benzidine rearrangement: a molecular orbital analysis.

Friday, January 18th, 2013

Michael Dewar[1] famously implicated a so-called π-complex in the benzidine rearrangement, back in the days when quantum mechanical calculations could not yet provide a quantitatively accurate reality check. Because this π-complex actually remains a relatively unusual species to encounter in day-to-day chemistry, I thought I would try to show in a simple way how it forms.

pi-complex

I am actually illustrating it with the benzidine rearrangement of monoprotonated PhNHOPh, which I dealt with in the previous post, if only because the energy of this π-complex relative to monoprotonated PhNHOPh is amazingly low (in other words, it is not one of these high energy molecules which only exist in the virtual world of computational modelling). The mechanism can be conceptually broken down to considering how the N-O bond can be cleaved in one of three ways. Route A is the homolytic route to give a 4-biradical (in one of the possible resonance forms), which of course can couple to form a 4,4′-biphenyl. Route B is a heterolytic route in which the two electrons from the N-O σ-bond are retained by 1, whilst for route C this electron pair is retained by 4.

These two fragments can then interact in several ways to form the π-complex. Here I will illustrate just the two closed shell options (B/C), whilst recognising that there may also be contribution from the open shell biradical (in water as solvent, the two ionic configurations are clearly going to be stabilised by solvation and so may contribute relatively more than the non-polar radical-pair ).

Route B (green), overlapping the HOMO of 1 with the LUMO of 2 to create a new π-MO to be occupied by the two electrons extracted from the N-O σ-bond (a similar promotion of a σ- to a π-pair was noted in this post).
Route C (red), overlapping the HOMO of 4 with the LUMO of 3 to achieve the same result.

Route B
LUMO of 2. Click for 3D.	HOMO for π-complex. Click for 3D.
HOMO of 1. Click for 3D.	HOMO for π-complex. Click for 3D.
Route C
LUMO of 3. Click for 3D.	HOMO for π-complex. Click for 3D.
HOMO of 4. Click for 3D.	HOMO for π-complex. Click for 3D.

The relative weight of these two combinations is largely determined by the difference in energies between the two HOMO/LUMO pairs and their overlap. ΔE is different for the two combinations, being 0.021 Hartree (route B) and 0.091 (route C), with lower being better.

The overlap of the HOMO/LUMO (in either orbital combination) is almost perfect for the face-to-face π-stacking of the complex. Note that this π-π-stacked arrangement in effect returns some electrons to the N-O region, in what is now called σ-π conjugation, and which used to be called hyperconjugation (it also resembles the conjugation of a Si-C bond with a phenyl ring in the Wheland intermediate).

References

M. Dewar, and H. McNicoll, "Mechanism of the benzidine rearrangement", Tetrahedron Letters, vol. 1, pp. 22-23, 1959. https://doi.org/10.1016/s0040-4039(01)82765-9

Tags:energy, high energy molecules, Michael Dewar, Reaction Mechanism
Posted in Interesting chemistry | 2 Comments »

Why is N,O-diphenyl hydroxylamine (PhNHOPh) unknown?

Wednesday, January 16th, 2013

If you search e.g. Scifinder for N,O-diphenyl hydroxylamine (RN 24928-98-1) there is just one literature citation, to a 1962 patent. Nothing else; not even a calculation (an increasing proportion of the molecules reported in Chemical Abstracts have now only ever been subjected to calculation, not synthesis). A search of Reaxys also offers only one hit[1] reporting one unsuccessful attempt in 1963 to prepare this compound. Again, nothing else. Yet show this structure to most organic chemists, and I venture to suggest few would immediately predict this (unless they are experts on benzidine rearrangements).^‡

PhNHOPh

The eagle-eyed reader of this blog may have noticed my noting in previous posts that the benzidine rearrangement proper is normally promoted by double protonation, and that reaction via monoprotonation has a significantly higher barrier. So what are the corresponding predicted reaction barriers for PhNHOPh? I start in fact with catalytic monoprotonation. The calculations are at ωB97XD/6-311G(d,p)/SCRF=water (closed shell) level.

System	N-protonated	O-Protonated^‡
Reactant	0.0	11.3
TS N-O	7.3	17.4
π-complex	2.1	6.0
TS C-C	4.8	13.2
^‡Relative to N-protonated reactant, in kcal/mol.

So it seems that even monoprotonation (on nitrogen) results in a very small ΔG₂₉₈^‡ barrier to the formation of a π-complex and its subsequent facile breakdown to form a C-C bond. I had noted in the earlier post that Ghigo and co-workers[2] had found that with diprotonated diphenyl hydrazine, the resulting π-complex has some open shell (biradical) character. The calculations reported here on the monoprotonated system are done as closed shell, but any biradical character this might have will only serve to even further reduce the barriers seen in the table. So we may confidently conclude that even monoprotonated N,O-diphenyl hydroxylamine will rapidly rearrange. A follow-up investigation for the diprotonated route hardly seems necessary!

But here is a challenge: if one were able to prepare PhNHOPh in thoroughly deprotic conditions, might it be isolable? There is precedent; the keto form of phenol can indeed be isolated under such conditions.[3].

Here are some intrinsic reaction coordinates to finish with. Firstly, for the formation of the π-complex from N-protonated precursor:

Once formed, the π-complex collapses readily to the 4,4′-coupled biphenyl.

There may be another pathway which collapses to the 1,1′-coupled biphenyl which I have not found yet. A [3,3] sigmatropic rearrangement converting the 4,4′ to the 1,1′-biphenyl is higher in energy, but still just about accessible thermally.

To end, here is a question. Could one systematically identify “gaps” in the distribution of known molecules; species which appear as if they should exist, but have never been reported? Of these, the majority will no doubt be absent from the record simply because they uninteresting. But some, as here, are absent because they are too unstable to exist, unless (extreme?) precautions are taken to remove the factors responsible for their instability (in this case, protons). Cyclobutadiene was one such famous example (stabilised by coordination to a metal). Certainly, computation nowadays can help identify conditions for how such molecules might be isolated.

^‡In contrast, PhNHSPh (N-Phenylbenzenesulfenamide) is a well known species[4].

References

J.R. Cox, and M.F. Dunn, "The chemistry of O,N-diarylhydroxlamines - I", Tetrahedron Letters, vol. 4, pp. 985-989, 1963. https://doi.org/10.1016/s0040-4039(01)90757-9
G. Ghigo, S. Osella, A. Maranzana, and G. Tonachini, "The Mechanism of the Acid‐Catalyzed Benzidine Rearrangement of Hydrazobenzene: A Theoretical Study", European Journal of Organic Chemistry, vol. 2011, pp. 2326-2333, 2011. https://doi.org/10.1002/ejoc.201001636
B. Miller, "Preparation of the Ketone Tautomer of a Phenol by a Cope Rearrangement1", Journal of the American Chemical Society, vol. 87, pp. 5515-5516, 1965. https://doi.org/10.1021/ja00951a064
I. Brito, A. Cárdenas, A. Mundaca, M. López-Rodríguez, and A. Reyes, "2-Iodo-N-(2-nitrophenylsulfanyl)aniline", Acta Crystallographica Section E Structure Reports Online, vol. 64, pp. o1387-o1387, 2008. https://doi.org/10.1107/s1600536808019491

Tags:energy, Historical, metal, pericyclic, Reaction Mechanism
Posted in Interesting chemistry | 7 Comments »

The Benzidine rearrangement. Computed kinetic isotope effects.

Friday, January 11th, 2013

Kinetic isotope effects have become something of a lost art when it comes to exploring reaction mechanisms. But in their heyday they were absolutely critical for establishing the mechanism of the benzidine rearrangement[1]. This classic mechanism proceeds via bisprotonation of diphenyl hydrazine, but what happens next was the crux. Does this species rearrange directly to the C-C coupled intermediate (a concerted [5,5] sigmatropic reaction) or does it instead form a π-complex, as famously first suggested by Michael Dewar[2] [via TS(NN] and only then in a second step [via TS(CC)] form the C-C bond? Here I explore the isotope effects measured and calculated for this exact system.

benzidine-KIE

It boils down to the following. It was supposed that if the mechanism was a concerted [5,5] sigmatropic shift, then both the N-N and the C-C bonds would be breaking/forming at the transition state and both N and C isotope effects would be expected. However, if a π-complex were formed, then either TS(NN) OR TS(CC) would be the rate determining step, and so either a NN OR a CC isotope effect should manifest, but not BOTH. The experiment carried out by Henry Shine and colleagues was thus expected to be the definitive one.[3] The results (in aqueous ethanol, at 273K) revealed the following: k(²H/¹H) = 0.962, k(¹⁴C/¹²C)^‡ = 1.013, k(¹³C/¹³C) = 1.013, k(¹⁵N/¹⁴N) = 1.041. This might have appeared to prove conclusively that the reaction was concerted, involving both the C-C and N-N bonds; in other words a [5,5] sigmatropic rearrangement.

The quantum mechanical (closed shell) surface reveals only two separate transition states, TS(NN) and TS(CC), and so at first sight seems to contradict the experimental isotope inference. But the experimental values are very unlikely to be wrong. So how can one reconcile these two methods? Well, the answer is not to give up, but to calculate the isotope effects for BOTH transition states, and see if either of them matches the experimental result. Here are these calculations:

TS	k(²H/¹H)	k(¹⁴C/¹²C)	k(¹³C/¹³C)	k(¹⁵N/¹⁴N)
CC	0.946	1.050	1.050	1.032
NN	1.002	1.008	1.007	1.075
Expt	0.962	1.013	1.013	1.041

The match between experiment and theory for TS(CC) is reasonable (given the approximations in both the theory and the difficulty of the experiments and ensuring isotopic purities) but not so for TS(NN). But TS(CC) is a “stepwise-concerted” reaction as a closed shell singlet; as shown in the IRC computed from TS(CC).

Yamabe and co[4] have come to similar conclusions (their model used a dication rather than an ion-pair). In the latest twist, Ghigo et al[5] used the same model as here (HCl to provide protonation as an ion-pair) but identified biradical (radical-cation) character at the transition state. The latter group also calculated kinetic isotope effects[6] for the open shell biradical TS, finding an even better match with experiment than above.

So this see-saw mechanism has oscillated between a stepwise π-complex, then a direct [5,5] rearrangement and in more recent times using computational modelling, a concerted [5,5] sigmatropic proceeding via an initially formed π-complex, and (finally) via a multi-step mechanism proceeding through a biradical π-complex and involving radical coupling, which nevertheless appears to behave in some aspects as a concerted [5,5] rearrangement. It is fascinating that a simple diprotonation of a hydrazine could so readily induce biradical character, and that such an apparently simple reaction could have so many twists and turns!

^‡ For one ¹⁴C-¹²C pair.

References

H.J. Shine, H. Zmuda, K.H. Park, H. Kwart, A.G. Horgan, and M. Brechbiel, "Benzidine rearrangements. 16. The use of heavy-atom kinetic isotope effects in solving the mechanism of the acid-catalyzed rearrangement of hydrazobenzene. The concerted pathway to benzidine and the nonconcerted pathway to diphenyline", Journal of the American Chemical Society, vol. 104, pp. 2501-2509, 1982. https://doi.org/10.1021/ja00373a028
M. Dewar, and H. McNicoll, "Mechanism of the benzidine rearrangement", Tetrahedron Letters, vol. 1, pp. 22-23, 1959. https://doi.org/10.1016/s0040-4039(01)82765-9
W. Subotkowski, L. Kupczyk-Subotkowska, and H.J. Shine, "The benzidine and diphenyline rearrangements revisited. 1-14C and 1,1'-13C2 kinetic isotope effects, transition state differences, and coupled motion in a 10-atom sigmatropic rearrangement", Journal of the American Chemical Society, vol. 115, pp. 5073-5076, 1993. https://doi.org/10.1021/ja00065a018
S. Yamabe, H. Nakata, and S. Yamazaki, "π Complexes in benzidine rearrangement", Organic & Biomolecular Chemistry, vol. 7, pp. 4631, 2009. https://doi.org/10.1039/b909313c
G. Ghigo, A. Maranzana, and G. Tonachini, "A change from stepwise to concerted mechanism in the acid-catalysed benzidine rearrangement: a theoretical study", Tetrahedron, vol. 68, pp. 2161-2165, 2012. https://doi.org/10.1016/j.tet.2012.01.014
G. Ghigo, S. Osella, A. Maranzana, and G. Tonachini, "The Mechanism of the Acid‐Catalyzed Benzidine Rearrangement of Hydrazobenzene: A Theoretical Study", European Journal of Organic Chemistry, vol. 2011, pp. 2326-2333, 2011. https://doi.org/10.1002/ejoc.201001636

Tags:Henry Shine, Michael Dewar, Reaction Mechanism, TS(CC), Yamabe and co
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A conflation of concepts: Conformation and pericyclic.

Thursday, January 10th, 2013

This is an interesting result I got when studying the [1,4] sigmatropic rearrangement of heptamethylbicyclo-[3.1.0]hexenyl cations. It fits into the last lecture of a series on pericyclic mechanisms, and just before the first lecture on conformational analysis. This is how they join.

The experiment it relates to[1] may well be a contender for the top ten list of most influential experiments ever conducted in chemistry. At -40°C, the ¹H NMR spectrum of this species has three peaks, at δ2.06, 1.57 and 1.13 ppm with an integral ratio of 15:3:3. The five basal methyls are averaged to 2.06 ppm, whereas those marked above as Me_a and Me_b exhibit distinct separate resonances. At -90°C, the five basal methyls split into peaks at δ2.48, 2.02, 1.66, in the integral ratio of 6:3:6. This indicates a process that is slow at the lower temperature but becomes fast (on the NMR time scale) at the higher temperature. The process must retain the individual identity of Me_a and Me_b.

The explanation is of course that a pericyclic [1,4] sigmatropic shift occurs. As a four electron process, this must have one antarafacial component, and this is by far easier to achieve by inverting the configuration at the migrating carbon centre. To convince oneself that this process does indeed retain the individual identity of Me_a and Me_b, an IRC of the reaction can be computed (ωB97XD/6-311G).

The energy profile is smooth and springs no surprises. The barrier is about right for the temperatures noted above.

But the RMS gradient norm along the IRC is unexpected.

Between the limits IRC ± 9, the profile is that of a reaction, involving bonds breaking and forming.
In the range IRC ± (9 – 15), unexpected features appear (hidden intermediates if you check this post). A whole plethora of them. This is the conformational region where the methyl flags start waving (and no bonds are formed or broken). If you watch the animation above very carefully, you will note that the methyl groups start rotating at the start and at the end of the migration, at a stage when the ring has an allyl cation. This delocalised cation has a different impact upon the conformation of the methyl groups from that of the transition state, where the charge now resides largely on the migrating carbon, and the ring now has just a neutral butadiene. This latter imparts a different conformational preference upon the methyl groups. You can see an orbital analysis of these effects at this post.
But perhaps the most surprising aspect of all of this is that each methyl flag waves at a different time from the others; first one waves, then the second and then the third. The two remaining basal methyls (attached to sp³ carbons) do not wave at all.

So this classic reaction is not just a pericyclic exemplar, it also illustrates nicely and concisely the conformational analysis of methyl groups interacting with an unsaturated system. Two for the price of one so to speak.

References

R.F. Childs, and S. Winstein, "Ring opening and fivefold degenerate scrambling in hexa- and heptamethylbicyclo[3.1.0]hexenyl cations", Journal of the American Chemical Society, vol. 90, pp. 7146-7147, 1968. https://doi.org/10.1021/ja01027a059

Tags:conformational analysis, energy profile, pericyclic, Reaction Mechanism, Tutorial material
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Hidden intermediates in the benzidine rearrangement. The monoprotonated mechanism.

Tuesday, January 8th, 2013

Eagle-eyed footnote readers might have spotted one at the bottom of the post on the benzidine rearrangement. I was comparing the N-N bond lengths in crystal structures of known diprotonated hydrazines (~1.45Å) with the computed N-N bond length at the start point of the intrinsic reaction coordinate for the [5,5] sigmatropic rearrangement of di-N-protonated diphenylhydrazine (the active species in the benzidine rearrangement itself), which was some 1Å longer. This post explores the implications of this oddity.

benzidine

My start point however is actually the mono-N-protonated system. The IRC for the calculated transition state is shown below. The activation barrier is a lot higher than with the diprotonated route, but I want to bring to your attention a feature at IRC = +5 to +3. At this point the RMS gradient norm dips, approaching but not quite reaching zero. This is what is called a hidden intermediate, an intermediate that does not quite form.^‡ It is in this region that the N-N bond length changes from the value of about 1.45Å for the monoprotonated hydrazine, to around 2.5Å at the point of the “hidden intermediate”. This represents the formation of the π-π-stacked complex as the preamble to the actual rearrangement, the transition state for which is of course reached at IRC =0.0. For this system, the [5,5] sigmatropic is actually slightly higher ( ΔG^‡₂₉₈ +2.4 kcal/mol) than the competing [3,3] rearrangement, which also shows that hidden intermediate ( at IRC ~+2.0). This close balance between the [3,3] and the [5,5] mechanisms suggests that factors such as ring substituents, counter-ion, solvent etc may in fact be able to swing this balance one way or the other.

The 5,5, sigmatropic rearrangement of monoprotonated diphenylhydrazine. Click for 3D

The 3,3 sigmatropic rearrangement of monoprotonated diphenylhydrazine. Click for 3D.

Which brings us back to the diprotonated species, the one with the N-N bond length of 2.53Å. This is a stable minimum (i.e. the RMS gradient norm is zero) with no imaginary frequencies computed, and hence it is no longer a hidden intermediate, but an exposed π-complex. Adding that second proton has stabilised it considerably. It is higher in ΔG₂₉₈ than the anti-conformation of diprotonated diphenylhydrazine by 6.1 kcal/mol, the latter having the normal N-N bond length of 1.46Å. The free energy barrier from the π-complex to the transition state for [5,5] rearrangement (shown in previous post) is a mere 2.4 kcal/mol. The barrier from the same π-complex to the transition state (N-N length 1.97Å) leading back to N-N diprotonated diphenylhydrazine is also small, 3.1 kcal/mol, so this π-complex is bounded only by small barriers and hence is very unlikely to be directly detected.

The benzidine π-complex. Click for 3D.	Anti-diprotonated diphenyl hydrazine. Click for 3D.
Transition state between π-complex and N-N diprotonated diphenyhydrazine. Click for 3D.

To conclude, mono-protonated diphenyl hydrazine^† rearranges to the 4,4′-diaminobiphenyl via the so-called benzidine rearrangement by a concerted process that involves a hidden π-complex forming before the transition state is reached. Diprotonation exposes this hidden complex formed from diphenylhydrazine. This complex is the true starting point for the [5,5] sigmatropic rearrangement (if it can still be called that). The overall reaction becomes more exothermic by in effect separating the two positive charges resulting from nitrogen diprotonation onto the two phenyl rings, an affect which also encourages the π-complex to form.

^‡Another good example of such a species is the intermediate carbocation in the solvolysis of t-butyl chloride. This too is hidden.

^†It is rather curious that Ph-NH-O-Ph is in effect unknown (apart from one patent). Could it be that it cannot be prevented from rearranging by the same mechanism as Ph-NH-NH-Ph?

Tags:free energy barrier, Reaction Mechanism
Posted in Uncategorized | 3 Comments »

The mechanism of the Benzidine rearrangement.

Sunday, January 6th, 2013

The benzidine rearrangement is claimed to be an example of the quite rare [5,5] sigmatropic migration[1], which is a ten-electron homologation of the very common [3,3] sigmatropic reaction (e.g. the Cope or Claisen). Some benzidine rearrangements are indeed thought to go through the [3,3] route[2]. The topic has been reviewed here[3].

benzidine

In this post, I offer a calculated transition state and IRC for this reaction, to see what insights might accrue. How was this obtained?

At the ωB97XD/6-311G(d,p)/SCRF=water level. This procedure would allow for any dispersion-like effects to be allowed for in the π-π-stacking.
The rearrangement is normally promoted by acid, and the active species is thought to be diprotonated[4]^‡ (although monoprotonated catalysis is also observed[1]. Here I report just the diprotonated route, together with chloride anions to balance the charges, and have added a continuum water field to allow this double ion-pair to be at least partially stabilised.
The rate determining step is the N-N cleavage/C-C bond formation. This is followed by presumed rapid proton transfers, which are not modelled here.

The [5,5] transition state for the benzidine rearrangement. Click for 3D.

This [5,5] transition state is 2.9 kcal/mol lower in ΔG^‡₂₉₈ than the transition state for the isomeric [3,3] rearrangement. The NCI (non-covalent-interactions) shows the forming C-C bond to be on the border of covalent, and non-covalent (blue), but that the π-π-stacking region is all weakly attractive (green). You can also observe the strong hydrogen bonds between the chloride anion and an N-H group (blue), and the weak attractive zones between the two nitrogen centres, between the chloride and the ortho-C-H hydrogens, and even between the two chloride anions (blue-green or green). I should point out that the initial position for these anions was over the aryl ring, but they migrated to the NH region during optimisation of the transition state.

NCI surface. Click for 3D.

The molecular electrostatic potential (isosurface = 0.11 au) shows both aryl rings as a single unit attracted by a positive potential (blue)

Calculated electrostatic potential. Click for 3D.

The highest-occupied molecular orbital shows the two bonds involved in the [5,5] shift (N-N and C-C) are both bonding, but more significantly, the central region of the two stacked aryl rings is also bonding. This is a clear manifestation of a π-complex, which the benzidine rearrangement has often (and it has to be said controversially) described as, and which elevates this particular reaction from that of a simple bond forming/bond cleaving sigmatropic. Another way of looking at it is that secondary orbital interactions (such as often invoked in Diels-Alder cycloadditions) are exceptionally important here.

HOMO for 5,5 benzidine rearrangement. Click for 3D.

The LUMO is strongly antibonding in that region; indeed adding two electrons to form a 12-electron process would be strongly destabilising. In this regard, this unusual sigmatropic reaction follows the same 4n+2 electron rule as more conventional ones.

LUMO. Click for 3D.

The next two diagrams illustrate the competing (higher energy) [3,3] shift, which also has some π-complex character.

A [3,3] alternative to the benzidine rearrangement. Click for 3D.

NCI surface for 3,3 rearrangement. Click for 3D.

I will end with three autobiographical notes.

The benzidine rearrangement was one of the earliest reactions I did in my home laboratory, at the age of about 13. As I recollect, I prepared about 1.5 grams (blissfully ignorant of how carcinogenic it is), and used it via diazotization to couple to phenol. My fascination with chemistry most certainly started with colour (and how to express the bonding in nitric oxide).
About eight years later, I was about to commence my Ph.D. studies. The objective was to use kinetic isotope effects to infer the structure of transition states. In my case (proton transfers to indoles) I never did achieve this objective. But it is noteworthy that the mechanism of the benzidine rearrangement was largely unravelled using such isotopic studies.
By 1974 as a post-doctoral researcher, I had moved on to studying mechanisms using quantum theory and had decided that it was easier to invert the use of isotope effects by predicting a transition structure using this method, and then seeing if the computed isotope effects matched the experiment. We did this for the Diels-Alder reaction[5] and more generally[6], and then for some gas-phase eliminations[7], this latter being my first entirely independent publication.
So, putting all this together, one might infer that armed with a computed transition state structure for the benzidine rearrangement, it is trivial to compute the kinetic isotope effects and hence to see if they correspond to those measured. You might expect a report on this in a future post here.

^‡ Crystal structures of diprotonated dimethyl hydrazines[4] show a N-N bond length of ~1.45Å (typical counter-anions being nitrate, perchlorate or sulfate). That calculated for the diprotonated diphenyl hydrazine is ~2.5Å, which suggests that with the phenyl group, electrons from the N-N region may be borrowed to contribute to the π-π-complex.

References

H.J. Shine, K.H. Park, M.L. Brownawell, and J. San Filippo, "Benzidine rearrangements. 19. The concerted nature of the one-proton rearrangement of 2,2'-dimethoxyhydrazobenzene", Journal of the American Chemical Society, vol. 106, pp. 7077-7082, 1984. https://doi.org/10.1021/ja00335a035
H.J. Shine, L. Kupczyk-Subotkowska, and W. Subotkowski, "Heavy-atom kinetic isotope effects in the acid-catalyzed rearrangement of N-2-naphthyl-N'-phenylhydrazine. Rearrangement is shown to be a concerted process", Journal of the American Chemical Society, vol. 107, pp. 6674-6678, 1985. https://doi.org/10.1021/ja00309a041
H.J. Shine, "Reflections on the π‐complex theory of benzidine rearrangements", Journal of Physical Organic Chemistry, vol. 2, pp. 491-506, 1989. https://doi.org/10.1002/poc.610020702
C.M. Sabaté, and H. Delalu, "Energetic Salts of Symmetrical Dimethylhydrazine (SDMH)", European Journal of Inorganic Chemistry, vol. 2012, pp. 866-877, 2011. https://doi.org/10.1002/ejic.201101115
M.J.S. Dewar, S. Olivella, and H.S. Rzepa, "Ground states of molecules. 49. MINDO/3 study of the retro-Diels-Alder reaction of cyclohexene", Journal of the American Chemical Society, vol. 100, pp. 5650-5659, 1978. https://doi.org/10.1021/ja00486a013
S.B. Brown, M.J.S. Dewar, G.P. Ford, D.J. Nelson, and H.S. Rzepa, "Ground states of molecules. 51. MNDO (modified neglect of diatomic overlap) calculations of kinetic isotope effects", Journal of the American Chemical Society, vol. 100, pp. 7832-7836, 1978. https://doi.org/10.1021/ja00493a008
H.S. Rzepa, "MNDO SCF-MO calculations of kinetic isotope effects for dehydrochlorination reactions of chloroalkanes", Journal of the Chemical Society, Chemical Communications, pp. 939, 1981. https://doi.org/10.1039/c39810000939

Tags:higher energy, Historical, pericyclic, Reaction Mechanism, π-complex
Posted in Interesting chemistry | 4 Comments »

Sharpless epoxidation, enantioselectivity and conformational analysis.

Thursday, January 3rd, 2013

I return to this reaction one more time. Trying to explain why it is enantioselective for the epoxide product poses peculiar difficulties. Most of the substituents can adopt one of several conformations, and some exploration of this conformational space is needed.

sharpless-binuclear

Amongst the conformational possibilities are the two rotations shown below. The blue rotates the ester with respect to the Ti-O-C unit, and the red rotates within the ester group itself. In fact the conformations of esters almost invariably adopt the first conformation shown, a s-cis orientation where one lone pair from the alkoxy group is anti to the axis of the carbonyl group (red rotation). Crystal structures of binuclear titanoxy compounds show both options for the blue rotation. sharpless-conf

One might imagine that there are two rotations about the C-O and O-Ti bonds in the iPr-O-Ti fragment as well. Whilst some of the many permutations are precluded simply on steric grounds, this still leaves a lot of possibilities. I have certainly not explored anything like the full set, but felt it worth reporting two conformations which have lower energies than the ones I reported in this post. If I find any yet lower in energy, I will add a postscript here.

New conformations (hydrogens removed for clarity)
(R). Click for 3D	(S). Click for 3D.
Old conformations
(R). Click for 3D.	(S). Click for 3D

The conformations differ in the regions indicated with a red arrow; the (R) being 10.1 and the (S) 7.5 kcal/mol lower in ΔG₂₉₈. Note how a change in conformation of just one group can “knock-on” to other groups. The relative energies (kcal/mol) of these two new conformations are shown below, broken down into three components.

Enantiomer	Total energy	Attractive dispersion energy	Free energy
R	+2.2	+2.9	+0.3
S	0.0	0.0	0.0

As before, (S) wins out clearly in terms of the dispersion attractions, which appears to be also reflected in the total energy of each system (in other words, differentiation from non-dispersion terms is not large). The free energy includes the entropy calculated from the normal vibrational modes using the rigid-rotor-harmonic-oscillator approximation. Whilst it too shows (S) to be the lower in energy, the distinction is less clear-cut than with the old conformations. One is often warned that the RRHO oscillator approximation is not good for molecules with many free rotors (which normally means about single bonds), although one normally might expect that comparing two very similar systems will result in a lot of cancellation of errors. But this result here does suggest that for the Sharpless system, which has many free-rotor groups, free energies might need taking with an extra dose of caution. I would also add that one does need to optimise the geometry of transition states for such systems with extraordinary accuracy; for these two examples, one does need to achieve values for the six “zero” translations and rotations of < 10 cm^-1, which can involve heroic efforts (as it did here!).

I end by reiterating my earlier conclusion. The Sharpless seems to be an example of a reaction which achieves stereospecificity by the accumulation of many very tiny effects (the dispersion attractions), and hence the use of a dispersion-corrected method is absolutely critical. It may also in part involve accumulation of another set of small effects contributing to the total entropy and hence free energy. What it appears not to be is a manifestation of a small number of larger effects (e.g. stereoelectronic alignments) which can be “named”. Chemistry by and large is always an attempt to achieve simple explanations by use of the latter; in other words developing simple heuristics or rules that can be transferred between systems. Where you have an effect that is in effect an accumulation of many terms, it is much more difficult to express this as simple transferable rules. Chemistry at such a level then is reduced simply to computing the sum of these small effects, rather than relying on simple rules. Have we perhaps reached this level with the Sharpless per-epoxidation? Would it be such fun if it were?

Tags:catalysis, conformational analysis, energy, epoxide product, free energy, Reaction Mechanism, similar systems, Tutorial material
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How to tame an oxidant: the mysteries of "tpap" (tetra-n-propylammonium perruthenate).

Monday, December 24th, 2012

tpap[1], as it is affectionately known, is a ruthenium-based oxidant of primary alcohols to aldehydes discovered by Griffith and Ley. Whereas ruthenium tetroxide (RuO₄) is a voracious oxidant[2], its radical anion countered by a tetra-propylammonium cation is considered a more moderate animal[3]. In this post, I want to try to use quantum mechanically derived energies as a pathfinder for exploring what might be going on (or a reality-check if you like).

tpap

A basic (i.e. simple) mechanism for oxidation of an alcohol by RuO₄ is shown above. Here I reality-check this mechanistic pathway with the help of ωB97XD/Def2-SVPF/SCRF=dichloromethane calculations. I should point out that since the mechanism is going to involve ion-pairs, it is particularly important to adopt a solvent=corrected model from the outset[4]. TS1 is the transition state for addition of the alcohol to the metal, a process which involves a synchronous proton transfer for the singlet electronic state.

TS1 as a singlet. Click for 3D

Next comes TS2, which involves a hydride abstraction with concomitant reduction of the oxidation number of Ru(VIII) to Ru(VI). It is higher in free energy than TS1 by 1.1 kcal/mol. The barrier corresponds to ΔG₂₉₈^‡ 37.1 kcal/mol. The process completes by low energy elimination of water (TS3) from the Ru(VI) species to give RuO₃, which either undertakes further oxidisation to give RuO₂, or might instead be re-oxidized back to RuO₄ by oxygen (or an amine N-oxide) to complete a catalytic cycle.

TS2 as a singlet. Click for 3D	–
TS2 as a triplet. Click for 3D

Right away, we have a problem; ΔG₂₉₈^‡37.1 kcal/mol is too high to be a realistic pathway, and yet RuO₄ is a known oxidant[2]. One way out is to see if the triplet state energy of this system might be lower. Whilst the triplet-state reactant is higher in energy (by 27.5 kcal/mol) , TS2 is lower and corresponds to a reduced barrier of ΔG₂₉₈^‡ 28.2 kcal/mol. Better, but a (small?) question mark still remains, since one would really expect the barrier to be ~20 kcal/mol or less for a “voracious oxidant”. Perhaps the incursion of triplets makes it indiscriminate? The spin density at the transition state is shown below, it extends across both oxygen, carbon and Ru.

ts2-triplet-spin

The tpap modification to this process is to use Ru(VII) in the form of a radical anion partnered with a quaternary ammonium cation. The basic reagent is therefore an ion-pair, hence the solvation approach mentioned earlier is needed to describe the energetics of such a species. The R alkyl groups here are modelled as methyl rather than propyl.

tpap1

TS2 for this radical-ion-pair is shown below, and it has ΔG₂₉₈^‡ 30.8 kcal/mol, 2.6 kcal/mol higher than for the un-moderated reagent. In this case, the higher-spin quartet states are higher in energy (by at least ~7.9 kcal/mol) and so do not participate.

The spin density for tpap-TS2 also reveals it to be concentrated on Ru and one oxygen. Little is transferred to the ethanol, and we might infer then that this TS corresponds to transfer of two-electrons from the ethanol to the Ru-oxidant. This corresponds to Ru(VII) being reduced to Ru(V), i.e. a 2-electron oxidation/reduction. Unfortunately, an attempt to chart the reaction across a whole reaction coordinate (IRC) failed with SCF-convergence problems, which might suggest a change in the spin-configuration during this process. A more sophisticated multi-configurational approach might be needed to properly establish the electron dynamics of what is turning out to be a more complex reaction than first seemed.

tpap-ts2-spin-density

It is time to sum up what might have been learnt.

A reality check on the energetics of a viable-looking mechanistic route can establish whether such a mechanism does have a low enough free-energy to be viable at (in this case) room temperatures.
In fact, observing that our initial mechanism had too high an energy led us to discover a triplet-state path that was significantly lower in energy. However, even this is still a bit too high.
The tpap-variation of the oxidant, which enforces a doublet-state upon the mechanism,has a barrier which appears to be similar to the triplet-state RuO₄ mechanism. This too may be too high in energy. At least we can probably rule out a quartet-state mechanism.
And so it seems appropriate to end here by noting that experimentally[3] the kinetics of tpap oxidations appear to be autocatalytic. The rate speeds up once some RuO₃ (or RuO₂) has been formed, and this suggests that perhaps a binuclear system containing two Ru atoms is a faster oxidant than the mononuclear variety. This reminds of the mechanism for Sharpless perepoxidation, where two metal centres were needed to control the stereochemistry.

So after all of this, we have not really found an explanation of why tpap is a more selective and moderate oxidant than the rapacious RuO₄. But perhaps this is because more complex models with more than one Ru-atom need to be constructed. This would in turn allow the oxidative hydride abstraction from the alcohol to occur in a larger (7) ring transition state, which is always the preferred geometry for such transfers. If I find such, I will report back here.

References

S.V. Ley, J. Norman, W.P. Griffith, and S.P. Marsden, "Tetrapropylammonium Perruthenate, Pr4N+RuO4 -, TPAP: A Catalytic Oxidant for Organic Synthesis", Synthesis, vol. 1994, pp. 639-666, 1994. https://doi.org/10.1055/s-1994-25538
D.G. Lee, U.A. Spitzer, J. Cleland, and M.E. Olson, "The oxidation of cyclobutanol by ruthenium tetroxide and sodium ruthenate", Canadian Journal of Chemistry, vol. 54, pp. 2124-2126, 1976. https://doi.org/10.1139/v76-304
D.G. Lee, Z. Wang, and W.D. Chandler, "Autocatalysis during the reduction of tetra-n-propylammonium perruthenate by 2-propanol", The Journal of Organic Chemistry, vol. 57, pp. 3276-3277, 1992. https://doi.org/10.1021/jo00038a009
J. Kong, P.V.R. Schleyer, and H.S. Rzepa, "Successful Computational Modeling of Isobornyl Chloride Ion-Pair Mechanisms", The Journal of Organic Chemistry, vol. 75, pp. 5164-5169, 2010. https://doi.org/10.1021/jo100920e

Tags:catalysis, energy, free energy, low energy elimination, metal, react freq, Reaction Mechanism, RuO4+ ethanol, triplet state energy, Tutorial material
Posted in Interesting chemistry | No Comments »

How to tame an oxidant: the mysteries of “tpap” (tetra-n-propylammonium perruthenate).

Monday, December 24th, 2012

tpap

TS1 as a singlet. Click for 3D

TS2 as a singlet. Click for 3D	–
TS2 as a triplet. Click for 3D

ts2-triplet-spin

tpap1

tpap-ts2-spin-density

It is time to sum up what might have been learnt.

A reality check on the energetics of a viable-looking mechanistic route can establish whether such a mechanism does have a low enough free-energy to be viable at (in this case) room temperatures.
In fact, observing that our initial mechanism had too high an energy led us to discover a triplet-state path that was significantly lower in energy. However, even this is still a bit too high.
The tpap-variation of the oxidant, which enforces a doublet-state upon the mechanism,has a barrier which appears to be similar to the triplet-state RuO₄ mechanism. This too may be too high in energy. At least we can probably rule out a quartet-state mechanism.
And so it seems appropriate to end here by noting that experimentally[3] the kinetics of tpap oxidations appear to be autocatalytic. The rate speeds up once some RuO₃ (or RuO₂) has been formed, and this suggests that perhaps a binuclear system containing two Ru atoms is a faster oxidant than the mononuclear variety. This reminds of the mechanism for Sharpless perepoxidation, where two metal centres were needed to control the stereochemistry.

References

S.V. Ley, J. Norman, W.P. Griffith, and S.P. Marsden, "Tetrapropylammonium Perruthenate, Pr4N+RuO4 -, TPAP: A Catalytic Oxidant for Organic Synthesis", Synthesis, vol. 1994, pp. 639-666, 1994. https://doi.org/10.1055/s-1994-25538
D.G. Lee, U.A. Spitzer, J. Cleland, and M.E. Olson, "The oxidation of cyclobutanol by ruthenium tetroxide and sodium ruthenate", Canadian Journal of Chemistry, vol. 54, pp. 2124-2126, 1976. https://doi.org/10.1139/v76-304
D.G. Lee, Z. Wang, and W.D. Chandler, "Autocatalysis during the reduction of tetra-n-propylammonium perruthenate by 2-propanol", The Journal of Organic Chemistry, vol. 57, pp. 3276-3277, 1992. https://doi.org/10.1021/jo00038a009
J. Kong, P.V.R. Schleyer, and H.S. Rzepa, "Successful Computational Modeling of Isobornyl Chloride Ion-Pair Mechanisms", The Journal of Organic Chemistry, vol. 75, pp. 5164-5169, 2010. https://doi.org/10.1021/jo100920e

Non covalent interactions in the Sharpless transition state for asymmetric epoxidation.

Wednesday, December 19th, 2012

The Sharpless epoxidation of an allylic alcohol had a big impact on synthetic chemistry when it was introduced in the 1980s, and led the way for the discovery (design?) of many new asymmetric catalytic systems. Each achieves its chiral magic by control of the geometry at the transition state for the reaction, and the stabilizations (or destabilizations) that occur at that geometry. These in turn can originate from factors such as stereoelectronic control or simply by the overall sum of many small attractions and repulsions we call dispersion interactions. Here I take an initial look at these for the binuclear transition state shown schematically below.

sharpless-binuclear

The NCI method was described recently[1] as a method for probing the non-covalent electron density in a molecule. It does this by cleverly filtering out the covalent density via computing a first derivative of the density ρ(r) called the reduced density gradient and taking the band of values appropriate for non-covalent densities. By inspecting the Laplacian of these densities at any point in space, the region can be characterised as attractive, repulsive or neutral. Visually, this information can be transformed into isosurfaces which are colour coded depending on whether the region is attractive (=blue to green) or repulsive (yellow to red). In the previous post, it turned out that the attractive contributions to the dispersion energies differed for the two diasteromeric transition states (in the conformations calculated) by about 2.6 kcal/mol. Shown below are the two NCI surfaces for these which allow one to get some insight into where this overall contribution might come from (together with weak hydrogen bonds and other non-covalent contributions).

(R)-diastereomer. Click for NCI surfaces

(S)-diastereomer. Click for NCI surfaces.

Yes, it is a very complex diagram, and you really do need to study it by obtaining the 3D model and rotating it around to explore the 3D space. I would note that it is possible to integrate the NCI function (see [2] for an example and leading references) and hence try to obtain further insights. I highlight just one here; the terminal =CH₂ of the allyl alcohol points into empty space for (R), but folds back to interact with the catalyst for (S).

Finally, in case you are asking how do I obtain an NCI surface, I have created a little web site where you can submit a computed (or indeed experimental) electron density cube for processing using Jmol. Give it a go and see how it works (and thanks to Julia Contreras-Garcia and Bob Hanson for putting this together).

References

E.R. Johnson, S. Keinan, P. Mori-Sánchez, J. Contreras-García, A.J. Cohen, and W. Yang, "Revealing Noncovalent Interactions", Journal of the American Chemical Society, vol. 132, pp. 6498-6506, 2010. https://doi.org/10.1021/ja100936w
J.L. Arbour, H.S. Rzepa, J. Contreras‐García, L.A. Adrio, E.M. Barreiro, and K.K.(. Hii, "Silver‐Catalysed Enantioselective Addition of OH and NH Bonds to Allenes: A New Model for Stereoselectivity Based on Noncovalent Interactions", Chemistry – A European Journal, vol. 18, pp. 11317-11324, 2012. https://doi.org/10.1002/chem.201200547

Tags:asymmetric catalytic systems, Bob Hanson, catalysis, Julia Contreras-Garcia, little web site, NCI, non-covalent-analysis, Reaction Mechanism, terminal =CH
Posted in Interesting chemistry | No Comments »

Henry Rzepa's blog

Posts Tagged ‘Reaction Mechanism’

The π-complex in the benzidine rearrangement: a molecular orbital analysis.

References

Why is N,O-diphenyl hydroxylamine (PhNHOPh) unknown?

References

The Benzidine rearrangement. Computed kinetic isotope effects.

References

A conflation of concepts: Conformation and pericyclic.

References

Hidden intermediates in the benzidine rearrangement. The monoprotonated mechanism.

The mechanism of the Benzidine rearrangement.

References

Sharpless epoxidation, enantioselectivity and conformational analysis.

How to tame an oxidant: the mysteries of "tpap" (tetra-n-propylammonium perruthenate).

References

How to tame an oxidant: the mysteries of “tpap” (tetra-n-propylammonium perruthenate).

References

Non covalent interactions in the Sharpless transition state for asymmetric epoxidation.

References

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