Posts Tagged ‘Functional groups’
Saturday, August 25th, 2018
Symbiosis between computation and experiment is increasingly evident in pedagogic journals such as J. Chemical Education. Thus an example of original laboratory experiments[1],[2] that later became twinned with a computational counterpart.[3] So when I spotted this recent lab experiment[4] I felt another twinning approaching.
The reaction under consideration is that between dec-2-enal and 2,4-dinitrobenzyl chloride as catalysed by an α,α-diphenylprolinol trimethylsilyl ester with addition of further base (di-isopropylamine?). The proposed mechanism can be seen in figure 7‡ of the journal article[4] and also scheme 2 of an earlier article.[5] The following is my interpretation of their published mechanism (the compound numbering is the same as in Figure 7).
- The initiating step is the condensation between the alkyl enal (1) and the prolinol derivative (3), with elimination of water and the formation of a positive iminium cation (5). One might wonder at this stage what the counter ion to this cation is.
- 5 then reacts with 2,4-dinitrobenzyl chloride (2) with apparent elimination of HCl to form 6. This corresponds to 1,4-Michael addition to 5 with the formation of the first new C-C bond and the creation of two new stereogenic centres.
- 6 then cyclises to form a second new C-C bond and a third new stereogenic centre as in 7.
- 7 is then hydrolysed to give the final product 4.
A total of three (starred) stereogenic centres are therefore created in 4, implying 23 = 8 steroisomers, arranged as four diastereomers and their enantiomers. A computational mechanistic analysis might strive to cast light on the following questions.
- Is the sequence shown in figure 7 reasonable? If not can a more reasonable cycle be constructed that has energetics corresponding to a facile reaction at 0°C?
- What are the predicted relative yields of the four possible diastereomeric products and do they match those observed?
- If R=α,α-diphenylprolinol trimethylsilyl ester, then this fourth chiral centre increases the total number of stereoisomers to 16, arranged in eight pairs of diastereomers. Does this result in the diastereomers of 4 forming with an excess of one enantiomer over the other (an ee ≠ 0)?
This post addresses just the first question (R=R’=H, R”=isopropylamine) leaving the other two questions for later analysis.
My analysis (figure above)♥ of the mechanism, as cast for computational analysis†, differs in various details from Figure 7/Scheme 2 of the published articles.[4],[5]
- The issue of defining a counterion to 5 is solved by in fact starting the cycle with proton abstraction from 2 by di-isopropylamine♦ to form a benzylic anion, as stabilized by the 2,4-dinitro groups and with the positive counter-ion being the protonated amine base.
- The next step is reaction between 1 and 3 to form an aminol 10, a tetrahedral intermediate.
- To remove water from this to form an iminium cation 5, one has to protonate the hydroxy group and this can now be done using the cationic ammonium species formed in step 5 above.
- The benzylic anion can now react with the iminium cation to form the first C-C bond and the first two stereocentres via 1,4-Michael addition to form 6
- The species 6 can now eliminate chloride anion to form the cyclopropyl iminium cation/anion pair 7, generating the 3rd stereogenic centre.
- Hydrolysis forms the product 4 and returns the system to the starting point in the catalytic cycle.
- Also included is whether an alternative mechanism is viable, involving elimination of Cl– from 8 to form a “carbene”, which could then potentially add to the alkene in 1.
The (relative) free energies of the transition states at the B3LYP+GD3BJ/6-311G(d,p)/SCRF=chloroform level shown in the table above (click on the thumbnail images to show the 3D model of each transition state) reveal that the highest point corresponds to TS3, a C-C bond forming reaction. This is noteworthy because it constitutes the reaction between an ion-pair, albeit ions which are both heavily stabilized by delocalisation. Since the reaction is known to proceed over 3 hours at 0°C, the activation barrier of 16.8 kcal/mol is also entirely reasonable. TS5, the putative formation of a carbene from the benzyl chloride, has a very high barrier and in fact cyclises to form 9. This pathway can therefore be safely ignored.
The next stage would be to investigate the stereochemical implications of this mechanism (atoms in 4 marked with a *) using the actual substituents for R and R’. Because the mechanism includes ion-pairs throughout, this does actually present some tricky issues. Unlike molecules with covalent bonds, where the shapes are relatively easy to predict, ion-pairs are more flexible and can often adopt a variety of poses, the relative energy of which is frequently determined simply by the magnitudes of their dipole moments.[6] If I manage to sort this out, I will report back here.
‡I would love to show you figure 7 here, but the publisher asserts that I would need to pay them $87.75 to do so and so you will have to acquire the article yourself to see it.
†Various guiding rules include constructing the entire catalytic cycle using exactly the same number of atoms so that the cycle can show only relative (free) energies and using neutral ion-pair models rather than just charged species alone.
♥Almost all the chemical diagrams on this blog for some ten years now have been in SVG (scalable vector graphics) format. Most modern web browsers for a number of years now have had excellent support for SVG. Until recently SVG could not be generated directly from a drawing program such as e.g. ChemDraw. Instead I saved as EPS (encapsulated postscript) and then used a program called Scribus to convert to SVG. In fact with Chemdraw V18.0, the direct conversion to SVG seems to be working very well, including honoring color maps. To scale up a diagram, click on it to open a new browser window containing only it and then use the browser zoom-in control to magnify it. Unlike e.g. a pixel image, SVG images magnify/scale correctly.
♣This relates to metadata as described in this post in performing a global search of any species matching this Gibbs Energy.
♦If the mechanism is set up without any base, then proton abstraction must occur directly from the benzyl chloride. Under these circumstances, the barrier for proton removal is 27.5 kcal/mol, whilst that for C-C bond formation is only 13.6.
References
- A. Burke, P. Dillon, K. Martin, and T.W. Hanks, "Catalytic Asymmetric Epoxidation Using a Fructose-Derived Catalyst", Journal of Chemical Education, vol. 77, pp. 271, 2000. https://doi.org/10.1021/ed077p271
- J. Hanson, "Synthesis and Use of Jacobsen's Catalyst: Enantioselective Epoxidation in the Introductory Organic Laboratory", Journal of Chemical Education, vol. 78, pp. 1266, 2001. https://doi.org/10.1021/ed078p1266
- K.K.(. Hii, H.S. Rzepa, and E.H. Smith, "Asymmetric Epoxidation: A Twinned Laboratory and Molecular Modeling Experiment for Upper-Level Organic Chemistry Students", Journal of Chemical Education, vol. 92, pp. 1385-1389, 2015. https://doi.org/10.1021/ed500398e
- M. Meazza, A. Kowalczuk, S. Watkins, S. Holland, T.A. Logothetis, and R. Rios, "Organocatalytic Cyclopropanation of (<i>E</i>)-Dec-2-enal: Synthesis, Spectral Analysis and Mechanistic Understanding", Journal of Chemical Education, vol. 95, pp. 1832-1839, 2018. https://doi.org/10.1021/acs.jchemed.7b00566
- M. Meazza, M. Ashe, H.Y. Shin, H.S. Yang, A. Mazzanti, J.W. Yang, and R. Rios, "Enantioselective Organocatalytic Cyclopropanation of Enals Using Benzyl Chlorides", The Journal of Organic Chemistry, vol. 81, pp. 3488-3500, 2016. https://doi.org/10.1021/acs.joc.5b02801
- J. Clarke, K.J. Bonney, M. Yaqoob, S. Solanki, H.S. Rzepa, A.J.P. White, D.S. Millan, and D.C. Braddock, "Epimeric Face-Selective Oxidations and Diastereodivergent Transannular Oxonium Ion Formation Fragmentations: Computational Modeling and Total Syntheses of 12-Epoxyobtusallene IV, 12-Epoxyobtusallene II, Obtusallene X, Marilzabicycloallene C, and Marilzabicycloallene D", The Journal of Organic Chemistry, vol. 81, pp. 9539-9552, 2016. https://doi.org/10.1021/acs.joc.6b02008
Tags:Ammonium, Benzyl group, Cations, chemical diagrams, Chemistry, condensation, final product, Functional groups, Iminium, Methyl group, Name reactions, Organic chemistry, possible diastereomeric products, relative energy, Vector Graphics, web browsers
Posted in Interesting chemistry | 9 Comments »
Wednesday, August 8th, 2018
White City is a small area in west london created as an exhibition site in 1908, morphing over the years into an Olympic games venue, a greyhound track, the home nearby of the BBC (British Broadcasting Corporation) and most recently the new western campus for Imperial College London.♣ The first Imperial department to move into the MSRH (Molecular Sciences Research Hub) building is chemistry. As a personal celebration of this occasion, I here dedicate three transition states located during my first week of occupancy there, naming them the White City trio following earlier inspiration by a string trio and their own instruments.
The chemistry revisits the mechanism of amide formation from an acid and an amine, which I first described on this blog about four years ago. I had constructed a model of one amine and one carboxylic acid, to which I added a further acid in recognition that proton transfers are a key aspect of the mechanism. When the model is quantified using quantum calculations (ωB97XD/6-311G(d,p)/SCRF=p-toluene) it resulted in a free energy barrier ΔG298‡ of about 22 kcal/mol. Re-reading what I wrote, I see I did rather gloss over this value, which implies a decently rapid reaction! In fact, the reaction occurs relatively slowly at the temperature of refluxing toluene. Perhaps some alarm bells should have been tinkling at this stage (although the sluggish reaction might for example instead be due to poor solubility) and so here I have a rethink of the model used to see if that modest barrier really is correct.
The new premise is to test if the required proton transfers can instead be mediated using a second molecule of amine instead of acid; thus two molecules of carboxylic acid are now accompanied by two of amine, one of which will be used to transfer protons. The second acid is retained to facilitate comparison. As before, the mechanism is characterised by three transition states and two tetrahedral intermediates. The new mechanism is summarised below, with TS1-3 being the White City Trio.
The free energies are summarised in the table below. TS3, the rate limiting step, is slightly lower in energy if the amine is used for the proton transfer than via carboxylic acid. This is the wrong direction; we really want the barrier to increase to explain the relative difficulty of the reaction as observed in refluxing toluene! Fear not however, the new barrier is indeed a much more sluggish 28.6 kcal/mol (30.5 using a larger basis set).
How did this happen? It’s the reactants! The original reactant model was based on the known structure of acetic acid dimer, with an amine weakly hydrogen bonded. Adding an extra amine now allows an entirely new motif to form, in which the amine disrupts the acetic dimer to form a cyclic system with a pair of very strong (-)O-H-N(+)-H-O(-) hydrogen bond units.† The original model did not have sufficient components to fully allow this to happen.
So the White City Trio achieve a performance which helps explain why a reaction is sluggish rather than facile (normally one strives to show the opposite). Perhaps however it should be the White City quartet, in recognition that the reactant also had a role to play?
♣A photograph of the building under construction can be seen here. ‡Def2-TZVPPD basis set. †There does not appear to be a recorded structure for methylammonium acetate. We hope to obtain one to check what the extended structure actually is. ♥I will elaborate an interesting new use of this value in a separate post.
Tags:acetic acid, Acid, Amide, Amine, carboxylic acid, Chemistry, Company: BBC, Company: British Broadcasting Corporation, energy, Ester, exhibition site, free energy barrier, Functional groups, Hydrogen bond, Imperial College, Imperial College London, Ionic product, Newspaper & Magazine Printing Services, Non-ionic product, Olympic games, Organic chemistry, White City Trio
Posted in Interesting chemistry | 6 Comments »
Wednesday, August 8th, 2018
White City is a small area in west london created as an exhibition site in 1908, morphing over the years into an Olympic games venue, a greyhound track, the home nearby of the BBC (British Broadcasting Corporation) and most recently the new western campus for Imperial College London.♣ The first Imperial department to move into the MSRH (Molecular Sciences Research Hub) building is chemistry. As a personal celebration of this occasion, I here dedicate three transition states located during my first week of occupancy there, naming them the White City trio following earlier inspiration by a string trio and their own instruments.
The chemistry revisits the mechanism of amide formation from an acid and an amine, which I first described on this blog about four years ago. I had constructed a model of one amine and one carboxylic acid, to which I added a further acid in recognition that proton transfers are a key aspect of the mechanism. When the model is quantified using quantum calculations (ωB97XD/6-311G(d,p)/SCRF=p-toluene) it resulted in a free energy barrier ΔG298‡ of about 22 kcal/mol. Re-reading what I wrote, I see I did rather gloss over this value, which implies a decently rapid reaction! In fact, the reaction occurs relatively slowly at the temperature of refluxing toluene. Perhaps some alarm bells should have been tinkling at this stage (although the sluggish reaction might for example instead be due to poor solubility) and so here I have a rethink of the model used to see if that modest barrier really is correct.
The new premise is to test if the required proton transfers can instead be mediated using a second molecule of amine instead of acid; thus two molecules of carboxylic acid are now accompanied by two of amine, one of which will be used to transfer protons. The second acid is retained to facilitate comparison. As before, the mechanism is characterised by three transition states and two tetrahedral intermediates. The new mechanism is summarised below, with TS1-3 being the White City Trio.
The free energies are summarised in the table below. TS3, the rate limiting step, is slightly lower in energy if the amine is used for the proton transfer than via carboxylic acid. This is the wrong direction; we really want the barrier to increase to explain the relative difficulty of the reaction as observed in refluxing toluene! Fear not however, the new barrier is indeed a much more sluggish 28.6 kcal/mol (30.5 using a larger basis set).
How did this happen? It’s the reactants! The original reactant model was based on the known structure of acetic acid dimer, with an amine weakly hydrogen bonded. Adding an extra amine now allows an entirely new motif to form, in which the amine disrupts the acetic dimer to form a cyclic system with a pair of very strong (-)O-H-N(+)-H-O(-) hydrogen bond units.† The original model did not have sufficient components to fully allow this to happen.
So the White City Trio achieve a performance which helps explain why a reaction is sluggish rather than facile (normally one strives to show the opposite). Perhaps however it should be the White City quartet, in recognition that the reactant also had a role to play?
♣A photograph of the building under construction can be seen here. ‡Def2-TZVPPD basis set. †There does not appear to be a recorded structure for methylammonium acetate. We hope to obtain one to check what the extended structure actually is. ♥I will elaborate an interesting new use of this value in a separate post.
Tags:acetic acid, Acid, Amide, Amine, carboxylic acid, Chemistry, Company: BBC, Company: British Broadcasting Corporation, energy, Ester, exhibition site, free energy barrier, Functional groups, Hydrogen bond, Imperial College, Imperial College London, Ionic product, Newspaper & Magazine Printing Services, Non-ionic product, Olympic games, Organic chemistry, White City Trio
Posted in Interesting chemistry | 6 Comments »
Tuesday, December 26th, 2017
Recollect the suggestion that diazomethane has hypervalent character[1]. When I looked into this, I came to the conclusion that it probably was mildly hypervalent, but on carbon and not nitrogen. Here I try some variations with substituents to see what light if any this casts.
I have expanded the resonance forms of diazomethane by one structure from those shown in the previous two posts (a form by the way not considered in the original article[1]) to include a nitrene. This takes us back to an earlier suggestion on this blog that HC≡S≡CH is not a stable species but a higher order saddle point which distorts down to a bis-carbene, together with the suggestion that hypervalent triple bonds have the option of converting four of the six electrons into two carbene lone pairs, replacing the triple bond with a single bond. This in turn harks back to G. N. Lewis’ 101 year old idea for acetylene itself!
To explore this mode, I start by replacing the terminal ≡N in diazomethane with a ≡C-Me group, which cannot absorb electrons into lone-pairs in the manner that nitrogen can. A ωB97XD/Def2-TZVPP calculation‡ reveals that the linear form is a transition state for interconversion into a carbene. The IRC for the process (below) shows this carbene is ~10 kcal/mol lower than the linear “hypervalent” form.
NBO analysis of this transition state reveals a similar orbital pattern to diazomethane itself, including a non-bonding orbital on the H2C carbon. The Wiberg carbon bond indices are 3.6764 and N 3.6454 and the bond orders C=N 1.1390 and N=CMe 1.6192.
ELF analysis of this transition state reveals the presence of two non-bonding pairs on the carbon atoms either side of the nitrogen but unshared with it, with populations of 1.19e and 1.37e (DFT). That nitrogen really does not like excess electrons! The four atoms C,N,C,C have ELF valence basins totalling 8.00, 6.94, 7.69 and 7.92e (DFT) or 8.07, 7.07 and 7.61e (CASSCF), suggesting that unlike diazomethane itself, the octet-excess induced hypervalence on carbon is slightly decreased.
Pumping even more electrons in by replacing the ≡C-Me group with ≡C-NH2 does not increase any hypervalence, but does induce more electrons to reside in “lone pairs”. Of the four atoms along the chain, three have “lone pairs” associated with them, a total of 4.83e that do not contribute to bonds (valence).
An electron withdrawing ≡C-CN group replacing the ≡C-NH2 reverses the effect of the latter, but this linear species is still a transition state for carbon isomerisation:
Finally, combining all we have learnt by adding in nitro groups on the first carbon. This is no longer a transition state but now a stable species; the sum of the ELF basin integrations around the carbon on the left reaches 8.95e, slightly higher than the dinitro-diazomethane discussed in the previous post. The numerical Wiberg atom bond indices are C 3.8713, N 3.6898, C 3.8503, C 3.9958 and N 3.0288 for the atoms along the chain, with the first nitrogen the “least-valent”.
So we see that “hypervalence”, or at least “octet-excess”, which is not exactly the same as hypervalence since it includes contributions from non-bonding electrons, is balanced on a knife-edge. Trying to increase the octet-excess by pumping electrons in turns the system into a transition state for carbene formation. Octet-excess is seen as a metastable property, to be relieved by geometric distortions where possible or localization of electrons into non-bonding lone pairs. And I remind yet again that no evidence has manifested in calculations of the molecules above that the central nitrogen of these diazomethane-like systems has any propensity for octet or valence-excess as implied by the formula C=N≡X.[1]
‡FAIR data for all calculations is available at DOI: 10.14469/hpc/3476
References
- M.C. Durrant, "A quantitative definition of hypervalency", Chemical Science, vol. 6, pp. 6614-6623, 2015. https://doi.org/10.1039/c5sc02076j
Tags:chemical bonding, Chemistry, diazo, Diazo compounds, Diazomethane, diazomethane-like systems, Functional groups, Hypervalent molecule, Molecular geometry, Organic chemistry, Recollects
Posted in Hypervalency | 8 Comments »
Tuesday, December 26th, 2017
Recollect the suggestion that diazomethane has hypervalent character[1]. When I looked into this, I came to the conclusion that it probably was mildly hypervalent, but on carbon and not nitrogen. Here I try some variations with substituents to see what light if any this casts.
I have expanded the resonance forms of diazomethane by one structure from those shown in the previous two posts (a form by the way not considered in the original article[1]) to include a nitrene. This takes us back to an earlier suggestion on this blog that HC≡S≡CH is not a stable species but a higher order saddle point which distorts down to a bis-carbene, together with the suggestion that hypervalent triple bonds have the option of converting four of the six electrons into two carbene lone pairs, replacing the triple bond with a single bond. This in turn harks back to G. N. Lewis’ 101 year old idea for acetylene itself!
To explore this mode, I start by replacing the terminal ≡N in diazomethane with a ≡C-Me group, which cannot absorb electrons into lone-pairs in the manner that nitrogen can. A ωB97XD/Def2-TZVPP calculation‡ reveals that the linear form is a transition state for interconversion into a carbene. The IRC for the process (below) shows this carbene is ~10 kcal/mol lower than the linear “hypervalent” form.
NBO analysis of this transition state reveals a similar orbital pattern to diazomethane itself, including a non-bonding orbital on the H2C carbon. The Wiberg carbon bond indices are 3.6764 and N 3.6454 and the bond orders C=N 1.1390 and N=CMe 1.6192.
ELF analysis of this transition state reveals the presence of two non-bonding pairs on the carbon atoms either side of the nitrogen but unshared with it, with populations of 1.19e and 1.37e (DFT). That nitrogen really does not like excess electrons! The four atoms C,N,C,C have ELF valence basins totalling 8.00, 6.94, 7.69 and 7.92e (DFT) or 8.07, 7.07 and 7.61e (CASSCF), suggesting that unlike diazomethane itself, the octet-excess induced hypervalence on carbon is slightly decreased.
Pumping even more electrons in by replacing the ≡C-Me group with ≡C-NH2 does not increase any hypervalence, but does induce more electrons to reside in “lone pairs”. Of the four atoms along the chain, three have “lone pairs” associated with them, a total of 4.83e that do not contribute to bonds (valence).
An electron withdrawing ≡C-CN group replacing the ≡C-NH2 reverses the effect of the latter, but this linear species is still a transition state for carbon isomerisation:
Finally, combining all we have learnt by adding in nitro groups on the first carbon. This is no longer a transition state but now a stable species; the sum of the ELF basin integrations around the carbon on the left reaches 8.95e, slightly higher than the dinitro-diazomethane discussed in the previous post. The numerical Wiberg atom bond indices are C 3.8713, N 3.6898, C 3.8503, C 3.9958 and N 3.0288 for the atoms along the chain, with the first nitrogen the “least-valent”.
So we see that “hypervalence”, or at least “octet-excess”, which is not exactly the same as hypervalence since it includes contributions from non-bonding electrons, is balanced on a knife-edge. Trying to increase the octet-excess by pumping electrons in turns the system into a transition state for carbene formation. Octet-excess is seen as a metastable property, to be relieved by geometric distortions where possible or localization of electrons into non-bonding lone pairs. And I remind yet again that no evidence has manifested in calculations of the molecules above that the central nitrogen of these diazomethane-like systems has any propensity for octet or valence-excess as implied by the formula C=N≡X.[1]
‡FAIR data for all calculations is available at DOI: 10.14469/hpc/3476
References
- M.C. Durrant, "A quantitative definition of hypervalency", Chemical Science, vol. 6, pp. 6614-6623, 2015. https://doi.org/10.1039/c5sc02076j
Tags:chemical bonding, Chemistry, diazo, Diazo compounds, Diazomethane, diazomethane-like systems, Functional groups, Hypervalent molecule, Molecular geometry, Organic chemistry, Recollects
Posted in Hypervalency | 8 Comments »
Monday, April 17th, 2017
Following on from my re-investigation of close hydrogen bonding contacts to the π-face of alkenes, here now is an updated scan for H-bonds to alkynes. The search query (dataDOI: 10.14469/hpc/2478) is similar to the previous one:
- QA is any of N,O,F,Cl.
- X is any atom, including metals and non-metals.
- The carbon atoms are both specified as 2-coordinate, and the C-C bond type as any.
- The distance is from the hydrogen (normalised) to the C-C centroid, restricted to < 2.5Å to capture just the shortest examples.
- The mean of the sines of the two angles subtended at the centroid is calculated to indicate whether the approach is orthogonal.
- The mean of the absolute value of the sines of the two angles subtended at each carbon is calculated to indicate how non-linear the X-C-C angle is.
- Other constraints are no disorder, no errors and R < 0.05.
First the intermolecular hits (38). Prominent short examples include:
In most of the stronger examples (blue), the approach of the hydrogen is perpendicular to the C-C bond centroid (X-axis of plot above). Many however exhibit significant bending (Y-axis of plot above) from linearity at the two carbons (~173°), mostly away from the H but in some examples towards the H!
Selected entries from the intra-molecular search (34 hits) are shown below. Perhaps due to the intra-molecular nature, the angle of approach of the H is more variable than the intermolecular examples and the bending of the erstwhile X-C-C angle is again prominent.
ωB97XD/Def2-TZVPP calculations of one intermolecular example, ICUTAC (two molecules, dataDOI: 10.14469/hpc/2482) and one intramolecular case, KIXFOO (dataDOI: 10.14469/hpc/2481). For the former, crystal packing compressions perhaps provide some shortening of the hydrogen bond and the molecule also includes an example of a short C-H to π interaction (obs[3] 2.63Å).
What is noticeable from reading the abstracts of the articles cited above is that these hydrogen bonds are rarely commented upon by the authors and it does seem that most of these close contacts are serendipitous (they were not designed). All are somewhat longer than the shortest distances encountered for alkenes and it would be interesting to establish if this is an intrinsic property of the triple bond or whether less effort has hitherto been expended on designing closer approaches.
‡ Not all entries have an assigned dataDOI at CCDC.
†CrossRef DOIs here are collected as a citation at the bottom of the post using the WordPress KCite plugin. Unfortunately for a few months now, this plugin has stopped recognising DataCite DOIs, which is why here they are treated differently from CrossRef DOIs. This is purely a current attribute of the KCite plugin and does not imply any fundamental difference in the two types of DOI, other than one tends to be used as persistent identifiers of journal articles and the other of datasets.
References
- M. Akita, M. Chung, A. Sakurai, S. Sugimoto, M. Terada, M. Tanaka, and Y. Moro-oka, "Synthesis and Structure Determination of the Linear Conjugated Polyynyl and Polyynediyl Iron Complexes Fp*−(C⋮C)<i><sub>n</sub></i>−X (X = H (<i>n</i>= 1, 2); X = Fp* (<i>n</i>= 1, 2, 4); Fp* = (η<sup>5</sup>-C<sub>5</sub>Me<sub>5</sub>)Fe(CO)<sub>2</sub>)<sup>1</sup>", Organometallics, vol. 16, pp. 4882-4888, 1997. https://doi.org/10.1021/om970538m
- J. Forniés, S. Fuertes, A. Martín, V. Sicilia, E. Lalinde, and M.T. Moreno, "Homo‐ and Heteropolynuclear Platinum Complexes Stabilized by Dimethylpyrazolato and Alkynyl Bridging Ligands: Synthesis, Structures, and Luminescence", Chemistry – A European Journal, vol. 12, pp. 8253-8266, 2006. https://doi.org/10.1002/chem.200600139
- R. Banerjee, R. Mondal, J.A.K. Howard, and G.R. Desiraju, "Synthon Robustness and Solid-State Architecture in Substituted <i>g</i><i>em</i>-Alkynols", Crystal Growth & Design, vol. 6, pp. 999-1009, 2006. https://doi.org/10.1021/cg050598s
- B. Xu, K. Bussmann, R. Fröhlich, C.G. Daniliuc, J.G. Brandenburg, S. Grimme, G. Kehr, and G. Erker, "An Enamine/HB(C<sub>6</sub>F<sub>5</sub>)<sub>2</sub> Adduct as a Dormant State in Frustrated Lewis Pair Chemistry", Organometallics, vol. 32, pp. 6745-6752, 2013. https://doi.org/10.1021/om4004225
- M.J. Pouy, S.A. Delp, J. Uddin, V.M. Ramdeen, N.A. Cochrane, G.C. Fortman, T.B. Gunnoe, T.R. Cundari, M. Sabat, and W.H. Myers, "Intramolecular Hydroalkoxylation and Hydroamination of Alkynes Catalyzed by Cu(I) Complexes Supported by <i>N</i>-Heterocyclic Carbene Ligands", ACS Catalysis, vol. 2, pp. 2182-2193, 2012. https://doi.org/10.1021/cs300544w
- R.D. Dewhurst, A.F. Hill, and M.K. Smith, "Heterobimetallic C<sub>3</sub> Complexes through Silylpropargylidyne Desilylation", Angewandte Chemie International Edition, vol. 43, pp. 476-478, 2004. https://doi.org/10.1002/anie.200352693
- T. Holtrichter-Rößmann, C. Rösener, J. Hellmann, W. Uhl, E. Würthwein, R. Fröhlich, and B. Wibbeling, "Generation of Weakly Bound Al–N Lewis Pairs by Hydroalumination of Ynamines and the Activation of Small Molecules: Phenylethyne and Dicyclohexylcarbodiimide", Organometallics, vol. 31, pp. 3272-3283, 2012. https://doi.org/10.1021/om3001179
Tags:alkene, alkyne, Functional groups, intra-molecular search, search query
Posted in crystal_structure_mining | 1 Comment »
Tuesday, April 11th, 2017
Following my conformational exploration of enols, here is one about a much more common molecule, a carboxylic acid.
The components of the search are shown as four queries below, which will be combined in various Boolean senses (DOI: 10.14469/hpc/2462).
- Query one defines the carboxylic acid, with 3-coordinate carbon specified at the carbonyl along with 1-coordinate for the carbonyl oxygen. Then the HO-C=O torsion (o° for the syn conformation shown on the left above and 180° for the anti-conformation shown on the right) and the length of the O-C bond as variables.
- Query two defines a contact as ≤ the sum of van der Waals radii between QA (=N,O,F,Cl) and the hydrogen of the carboxylic acid (pink).
- Query three defines a contact as ≤ the sum of van der Waals radii between QA-H (QA=N,O,F,Cl) and the oxygen of the acid (pink).
- Query four defines a temperature of <100K for the data collection temperature.
The first search uses just Query 1, with additional constraints of no errors, no disorder and R < 0.05.
This can then be focused by combining Query 1 + Query 4, which shows a clear preference for the syn conformation.
Next, Query 1 with NOT query 2, which restricts the search to carboxylic acids that do not have contacts to the hydrogen of the OH group. This excludes carboxylic acid dimers, as shown above. The predominant hot-spot now corresponds to the anti conformation.
Again this is narrowed using Query 4, which removes almost all the syn examples.
Now using Query 3 (as shown above), which restricts the search to examples where the oxygen of the HO group is itself not in contact with an acidic hydrogen. This allows carboxylic acid dimers. This now reveals the syn preference again.
At <100K reinforces this effect.
Finally, Query 1 and NOT query 2 (no dimers) and NOT query 3, where a smaller preference for anti is seen.
So it seems that an interesting difference emerges between enols and carboxylic acids in that when no hydrogen bonding to the HO group is allowed, an anti preference emerges. The electronic origins of this effect will be probed in a future post.
Tags:Acid, Alcohols, carboxylic acid, Chemistry, Enol, Functional groups, Organic chemistry, search uses
Posted in crystal_structure_mining | No Comments »
Sunday, October 9th, 2016
Previously, a mechanistic twist to the oxidation of imines using peracid had emerged. Time to see how substituents respond to this mechanism.
With X = NO2 100% oxaziridine and no nitrone is obtained experimentally; with X = NMe2 , the population is inverted with nitrone as the dominant product at 78%.[1] Calculations (ωB97XD/Def2-TZVPP/SCRF=dichloromethane), data collection DOI: 10.14469/hpc/1743[2] are summarised in the table. The initial model employs the simpler peracetic acid as oxidant (R=Me) and we see here a computed preference of 4.2 kcal/mol for oxiziridine when the aryl substituent X = NO2 (a ratio of 1024:1 in its favour) but reduced to 1.4 kcal/mol when X = NMe2. This hardly changes when the acid is changed from ethanoic to mCPBA (meta-chloroperbenzoic acid), the oxidant actually used in the experiments.
| Substituents |
π |
σ |
| R=Me, X=NO2 |
-4.2 |
0.0 |
| R=Me, X=NMe2 |
-1.4 |
0.0 |
| R=m-Cl-phenyl, X=NO2 |
-4.1 |
0.0 |
| R=m-Cl-phenyl, X=NMe2 |
-1.3 |
0.0 |
You can see from the transition state structures that π attack is helped by stacking between the aryl face of the m-chloroperbenzoic acid and the aryl group on the imine, whereas σ is not.
These results show that our proposed mechanism can reproduce the selectivity for formation of oxaziridine when the aryl group bears X=NO2 but misses the mark of predicting nitrone formation when X=NMe2. Experimentally nitrone is favoured by ΔΔG298 0.75 kcal/mol, whereas the calculation disfavours this by -1.3 kcal/mol. Is this discrepancy enough to sink this mechanistic model? Or might yet another variation on the mechanism, such shifting the proton from peracid to the X=NMe2 do the trick?
What I have tried to show here is how one can iterate towards a realistic mechanism by gradually refining the models so that more and more experimental observations are correctly predicted. Sometimes of course, it might be the experiment itself that has to be repeated and refined, although we have not quite reached that point yet with this example.
References
- D.R. Boyd, P.B. Coulter, N.D. Sharma, W. Jennings, and V.E. Wilson, "Normal, abnormal and pseudo-abnormal reaction pathways for the imine-peroxyacid reaction", Tetrahedron Letters, vol. 26, pp. 1673-1676, 1985. https://doi.org/10.1016/s0040-4039(00)98582-4
- H. Rzepa, "Ï or Ï nucleophilic reactivity of imines", 2016. https://doi.org/10.14469/hpc/1743
Tags:Functional groups, Imine, Nitrone, NME2, Oxaziridine
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Wednesday, September 28th, 2016
The story so far. Imines react with a peracid to form either a nitrone (σ-nucleophile) or an oxaziridine (π-nucleophile).[1] The balance between the two is on an experimental knife-edge, being strongly influenced by substituents on the imine. Modelling these reactions using the “normal” mechanism for peracid oxidation did not reproduce this knife-edge, with ΔΔG (π-σ) 16.2 kcal/mol being rather too far from a fine balance.
There are two general reasons why computational modelling using quantum mechanics may not match experimental outcome. Until perhaps 10 or so years ago, the culprits may often have been the approximations necessary to apply the theory, as bounded by the limitations of the CPU power of the then available computers to evaluate the associated equations. Nowadays, an equally likely explanation is that the molecular model for which these equations are solved is either wrong or maybe just incomplete. For an organic reaction, these models are initially set out by “arrow pushing” a possible mechanistic pathway. Such speculations have been a common feature of most new articles reporting the outcome of reaction experiments for perhaps 60 years now. It is now more common (but by no means universal) to augment this with a computational reality check. So previously, when I applied a reality check on the “standard” epoxidation mechanism, it did not pass the test.
So time to revise the mechanism, as per below. The difference is that the model includes an extra water molecule to facilitate proton transfers, with the imine now being protonated by the peracid to form a zwitterion, which collapses to an addition product and it is this species that rearranges to the final oxaziridine. Free energies relative to the reactant 1 are shown in red below.‡
The IRC for 2 (TS) is shown below, being a proton transfer mediated by the transfer agent (water in this case, but it could be also peracid or eventually the product acid) to form a ion-pair.
4 (TS) shows the collapse of the ion-pair to form an addition product across the imine.
6 (TS, below) is the most interesting and also the high point on the free-energy pathway (i.e. the rate determining step). The addition product cyclises to an oxaziridine as induced by the nitrogen lone pair helping to evict the acetate anion. This is followed at IRC ~7 by a transfer of the N-H proton back to the carboxylic acid, again using water as a transfer agent with the whole being part of a concerted but asynchronous mechanistic step.
Crucially, 6 (TS) is 23.4 kcal/mol below the oxaziridination transition state modelled without a prior proton transfer[2],[3] and even 7.6 kcal/mol below the transition state for nitrone formation.[4],[5]
So the original mechanism is now replaced by an alternative, which really only differs in the timing of how the acidic proton attached to the peracid responds to the process. By getting actively involved prior to the crucial reaction with the nitrogen lone pair of the imine, this proton enables a lower energy route to be established. We are now ready for the next “reality check” on these mechanisms, which are the effects of substituents on the imine. If these can be replicated, we can then really start to claim that computation has put the mechanism of this reaction onto a firmer footing than that based just on “arrow-pushing”.
‡Calculations (ωB97XD/Def2-TZVPP/SCRF=dichloromethane) for the species above are archived as a collection at DOI: 10.14469/hpc/1704[6] and individually at 1[7], 2 (TS)[8], 3[9], 4 (TS)[10], [11], 5[12], 6 (TS)[13],[14], 7[15].
References
- D.R. Boyd, P.B. Coulter, N.D. Sharma, W. Jennings, and V.E. Wilson, "Normal, abnormal and pseudo-abnormal reaction pathways for the imine-peroxyacid reaction", Tetrahedron Letters, vol. 26, pp. 1673-1676, 1985. https://doi.org/10.1016/s0040-4039(00)98582-4
- H. Rzepa, "Imine + peracetic acid, Ï attack + H2O, TS.", 2016. https://doi.org/10.14469/hpc/1698
- H. Rzepa, "Imine + peracetic acid, pi attack + H2O, TS. IRC", 2016. https://doi.org/10.14469/hpc/1701
- H. Rzepa, "Imine + peracetic acid,N attack + H2O, TS", 2016. https://doi.org/10.14469/hpc/1697
- H. Rzepa, "Imine + peracetic acid,N attack + H2O, TS IRC", 2016. https://doi.org/10.14469/hpc/1702
- H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O reactant", 2016. https://doi.org/10.14469/hpc/1695
- H. Rzepa, "Imine + peracetic acid, Ï attack zwitterion + H2O", 2016. https://doi.org/10.14469/hpc/1703
- H. Rzepa, "Imine + peracetic acid, Ï attack zwitterion + H2O intermediate", 2016. https://doi.org/10.14469/hpc/1696
- H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O IRC => C-O formation TS", 2016. https://doi.org/10.14469/hpc/1692
- H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O IRC => C-O formation TS IRC", 2016. https://doi.org/10.14469/hpc/1700
- H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O TS IRC, addition int", 2016. https://doi.org/10.14469/hpc/1690
- H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O TS", 2016. https://doi.org/10.14469/hpc/1694
- H. Rzepa, "Imine + peracetic acid, Ï attack zwitterion + H2O TS IRC", 2016. https://doi.org/10.14469/hpc/1693
- H. Rzepa, "Imine + peracetic acid, pi attack zwitterion + H2O TS IRC, oxaziridine product", 2016. https://doi.org/10.14469/hpc/1691
Tags:addition product, free-energy pathway, Functional groups, Imine, Nitrone, Nucleophile, Organic chemistry, Oxaziridine
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Thursday, September 22nd, 2016
Compounds with O-O bonds often have weird properties. For example, artemisinin, which has some fascinating stereoelectronics. Here is another such, recently in the news and known as HMTD (hexamethylene triperoxide diamine). The crystal structure was reported some time ago[1] and the article included an inspection of the computed wavefunction. However this did not look at the potential stereoelectronics in this species, which I now address here.
A ωB97XD/Def2-TZVPP calculation[2] can be analysed for the NBO-derived interaction terms. This identifies an electron donor (normally a bond or a lone pair) and its E(2) perturbation energy interaction with an acceptor (normally an empty σ* antibond). Here we are interested in the interaction between the nitrogen “lone pair” and the adjacent C-O σ* antibond, of which there are six in the molecule due to the D3 symmetry. E(2) is ~22.4 kcal/mol, which is a large effect (the equivalent value for the so-called anomeric interaction between an oxygen lone pair and a C-O antibond is ~18 kcal/mol). The effect of donation into the empty C-O σ* antibond is to weaken it, unless the effect is balanced by a reciprocal interaction in the opposing direction, which is often the case in sugar-derived anomeric effects. Sugars of course are thermally relatively stable. In the case of HMTD, the reverse effect would be an oxygen Lp donating into the N-C σ* antibond and this has the value of 14.5 kcal/mol. Since the two are not balanced, this presumably contributes to the very unstable nature of this molecule.
An alternative way of looking at what the electrons are up to is ELF, a function based on the electron density which identifies the centroids of electron basins. The red arrows point to the four basins associated with the nitrogen “lone pair” (mostly the dumb-bell-shaped p-atomic orbital, hence four basins), and the integration being 3.2e for each nitrogen. This is a rather odd number for a “lone pair”. There is undoubtedly something unusual about this wavefunction which has yet to be identified.
Finally, I ask how common the N(sp3)-C(sp3)-O-O structure motif might be? In fact the Cambridge structure database has 81 entries! The scatterplot below includes 51 of them (no disorder, no errors, R<0.05). No clear-cut conclusions emerge from these statistics, except just a hint that as the C-O distance gets longer, the N-C distance might get shorter and that shorter N-C lengths are associated with shorter O-O lengths.
References
- A. Wierzbicki, E.A. Salter, E.A. Cioffi, and E.D. Stevens, "Density Functional Theory and X-ray Investigations of P- and M-Hexamethylene Triperoxide Diamine and Its Dialdehyde Derivative", The Journal of Physical Chemistry A, vol. 105, pp. 8763-8768, 2001. https://doi.org/10.1021/jp0123841
- H. Rzepa, "HMTD Hexamethylenetriperoxidediamine D3 NBO", 2016. https://doi.org/10.14469/hpc/1663
Tags:Amines, Artemisinin, Chemistry, Functional groups, Hexamethylene triperoxide diamine, Organic chemistry, Organic peroxides, Peroxide, perturbation energy interaction, Stereoelectronics
Posted in Interesting chemistry | 1 Comment »
