Posts Tagged ‘Electrophile’
Tuesday, June 21st, 2016
This is a follow-up to the post on exploring the directing influence of (electron donating) substituents on benzene[1] with the focus on heteroaromatic rings such indoles, pyrroles and group 16 analogues (furans, thiophenes etc).
The search query is shown above (and is available here[2]). As before, the distance is compared from an electrophile, modelled as the hydrogen atom of an OH group, to both the carbon next to the heteroatom (C2) and the C3 carbon. The torsion is defined so as to ensure that the OH group is approaching the π-face of the ring. The other constraints are R < 0.1, no disorder and no errors and normalised H positions.
Firstly, indoles (as above). There are only a few hits, but even so one can see that they all cluster in the top left triangle, where the distance to C2 is always longer than to C3. Indeed, this is the known position for electrophilic substitution of indoles.
The search can be extended by removing the benzo group so as to also include pyrroles. More hits are obtained, and again most of them collect in the top left triangle. The hot spot indicates that the difference in lengths is ~0.3Å in favour of the 3-position, a very similar discrimination to that previously found for benzene groups with an electron donating substituent.
Next, the N atom is replaced by any atom from group 16 of the periodic table (i.e. O, S, etc). The scatter is now in both top left and bottom right triangles, which suggest much weaker discrimination between C2 and C3; if anything in favour of C2 (often the observed regiospecificities for such compounds).
Finally, pyridines. Only a slight bias towards the C2 position. With pyridines of course, the electrophile in fact first interacts with the nitrogen lone pair in the plane of the molecule, which perturbs the eventual outcome. So this crystallographic method is perhaps a better intrinsic probe than kinetic reactivity.
References
- H.S. Rzepa, "Discovering More Chemical Concepts from 3D Chemical Information Searches of Crystal Structure Databases", Journal of Chemical Education, vol. 93, pp. 550-554, 2015. https://doi.org/10.1021/acs.jchemed.5b00346
- H. Rzepa, "Search for HO interactions to indoles, pyrroles, furans, and thiophenes", 2016. https://doi.org/10.14469/hpc/665
Tags:Asymmetric hydrogenation, benzene, benzo, Electrophile, Furan, Indole, Pyridine, Pyrrole, search query, Simple aromatic rings, Substitution reaction, Thiophene
Posted in crystal_structure_mining | No Comments »
Wednesday, May 11th, 2016
I have previously commented on the Bürgi–Dunitz angle, this being the preferred approach trajectory of a nucleophile towards the electrophilic carbon of a carbonyl group. Some special types of nucleophile such as hydrazines (R2N-NR2) are supposed to have enhanced reactivity[1] due to what might be described as buttressing of adjacent lone pairs. Here I focus in on how this might manifest by performing searches of the Cambridge structural database for intermolecular (non-bonded) interactions between X-Y nucleophiles (X,Y= N,O,S) and carbonyl compounds OC(NM)2.
The search query[2] is shown above and involves plotting the distance from the nucleophilic atom (N above) to the carbon of the carbonyl group. The carbon is defined as having 3-coordination, one of which is O=C and two non-metal attachments. The torsion is constrained to values of |70-110|° to ensure that the approach of the nucleophile is approximately perpendicular to the plane of the carbonyl in order to overlap with the π*-orbital as electrophile. The pairwise sums of van der Waals radii are NC, 3.25; OC, 3.22 and SC, 3.5Å and the plots show all contacts shorter than these. The results of the searches are shown below.
The general observation is that the red hotspots do tend to come at trajectory angles of <100° and many are <90° such as the X=Y=N or X=Y=S examples. Given that the original Bürgi–Dunitz hypothesis (actually based on a small number of molecules synthesized for the purpose) proposed rather larger angles (105±5°) corresponding to optimum alignment of the nucleophile with the carbonyl π*-orbital, we might speculate whether the use of enhanced nucleophiles is the reason for the apparent decrease in the angle. And if so, what the underlying reasons would be.
I also cannot help but observe that the term supernucleophile is quite rare in the literature; SciFinder gives only 45 hits, but most are about neither hydrazines nor peroxides. There are also some unusual nucleophile varieties such as Cob(I)alamin[3], of which there are probably insufficient examples to reflect in the crystal structure statistics shown above. Given the interest in superbases, the relative lack of examples of unusual supernucleophiles seems surprising.
References
- G. Klopman, K. Tsuda, J. Louis, and R. Davis, "Supernucleophiles—I", Tetrahedron, vol. 26, pp. 4549-4554, 1970. https://doi.org/10.1016/s0040-4020(01)93101-1
- H. Rzepa, "Crystal structure search using enhanced nucleophiles", 2016. https://doi.org/10.14469/hpc/487
- K.P. Jensen, "Electronic Structure of Cob(I)alamin: The Story of an Unusual Nucleophile", The Journal of Physical Chemistry B, vol. 109, pp. 10505-10512, 2005. https://doi.org/10.1021/jp050802m
Tags:Bases, Bürgi–Dunitz angle, Carbonyl, Electrophile, Ester, Flippin–Lodge angle, Functional groups, hydrazine, non-metal attachments, Nucleophile, Physical organic chemistry, search query, Superbase
Posted in Chemical IT, crystal_structure_mining | 1 Comment »
Thursday, January 7th, 2016
This is the third and final study deriving from my Ph.D.[1]. The first two topics dealt with the mechanism of heteroaromatic electrophilic attack using either a diazonium cation or a proton as electrophile, followed by either proton abstraction or carbon dioxide loss from the resulting Wheland intermediate. This final study inverts this sequence by starting with the proton abstraction from an indolinone by a base to create/aromatize to a indole-2-enolate intermediate, which only then is followed by electrophilic attack (by iodine). Here I explore what light quantum chemical modelling might cast on the mechanism.
The concentration of I3– is used to follow the reaction, given by the expression: [I3–] = k1[B][indolinone]t – k-1/k2*ln[I3–] + const, where k2* = k2/715[I–] + k2' , the latter being the rate coefficient for the reaction between the enolate intermediate and I3–. With appropriate least squares analysis of this rate equation,‡ a value for k1 using either 1H or 2H (≡ D) isotopes can be extracted and this gives an isotope effect k1H/k1D of 6.3 ± 0.6. Note that this value does NOT depend on [B]. Here, I am going to try to see if I can construct a quantum mechanical model which reproduces this value.
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Model 1 uses just three water molecules as a proton relay (B3LYP+D3/Def2-TZVP/SCRF=water).
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Model 2 uses 2H2O.NaOH solvated by two extra passive water molecules. Since under these conditions, the NaOH is largely ionic, [B] ≡ [OH–]
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Model
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ΔG‡298 (ΔH‡298)
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kH/kD (298K)
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DataDOIs
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1
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28.0 (22.9)
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10.3
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[2],[3],[4]
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2
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2.5 (2.8)
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4.4
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[5],[6],[7]
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The plot of rate vs [B] shows[1] that the uncatalysed (water) rate is very slow (intercept passes more or less through zero) and the calculated free energy barrier (28.0 kcal/mol) confirms a slow rate at ambient temperatures. Note in the final (aromatized) product, there is a noticeable hydrogen bond between the 3-carbon and a water molecule (2.14Å). The calculated kinetic isotope effect[8] is substantially larger than observed experimentally for the base catalysed contribution.
In the presence of NaOH (standard state = 1 atm = 0.044M), the enthalpy barrier drops very substantially to 2.8 kcal/mol and the free energy to 2.5 kcal/mol. Similar behaviour was noted previously on this blog for the hydrolysis of thalidomide. Although the magnitude of the reduction in barrier in fact implies an extremely fast reaction, recollect that [B]=[OH–] appears in the rate equation and since its value is very much less than 0.044M, the observed rate is relatively slow.
The calculated KIE for the hydroxide catalysed mechanism is much smaller that for the water route, but also smaller than is observed. This is a value uncorrected for tunnelling, which given the small barrier might be significant.
These calculations show how a model for ionization of indolinone can be constructed, and used to e.g. probe the sensitivity of KIE to perturbations induced by ring substituents, which may form the basis of a future post.
‡This is a non-linear equation with kinetics that straddle zero and first order behaviour. In 1972, it was not easily possible to graph such functions in a manner where the slope of a linear plot would yield the rate constant. It was only computers and languages such as Fortran which allowed such non-linear least squares analysis of the rate. In the event, it turned out that the presence of 50% methanol in the mixed aqueous solutions was the cause; in other solvents the kinetics approximated zero order behavour very well.
References
- B.C. Challis, and H.S. Rzepa, "Heteroaromatic hydrogen exchange reactions. Part VIII. The ionisation of 1,3-dimethylindolin-2-one", Journal of the Chemical Society, Perkin Transactions 2, pp. 1822, 1975. https://doi.org/10.1039/p29750001822
- H.S. Rzepa, "C 10 H 17 N 1 O 4", 2016. https://doi.org/10.14469/ch/191786
- H.S. Rzepa, "C 10 H 17 N 1 O 4", 2016. https://doi.org/10.14469/ch/191765
- H.S. Rzepa, "C10H17NO4", 2016. https://doi.org/10.14469/ch/191784
- H.S. Rzepa, "C 10 H 20 N 1 Na 1 O 6", 2016. https://doi.org/10.14469/ch/191787
- H.S. Rzepa, "C 10 H 20 N 1 Na 1 O 6", 2016. https://doi.org/10.14469/ch/191782
- H.S. Rzepa, "C10H20NNaO6", 2016. https://doi.org/10.14469/ch/191785
- H. Rzepa, "Mechanisms and kinetic isotope effects for the base catalysed ionisation of 1,3-dimethyl indolinone.", 2016. https://doi.org/10.14469/hpc/202
Tags:Arenium ion, Bases, diazo, Diazonium compound, Electrophile, Electrophilic aromatic substitution, Equilibrium chemistry, Fortran, Indole, light quantum chemical modelling, Metal ions in aqueous solution, Nuclear physics, Simple aromatic rings, Solutions
Posted in Historical, reaction mechanism | No Comments »
Friday, April 17th, 2015
The knowledge that substituents on a benzene ring direct an electrophile engaged in a ring substitution reaction according to whether they withdraw or donate electrons is very old.[1] Introductory organic chemistry tells us that electron donating substituents promote the ortho and para positions over the meta. Here I try to recover some of this information by searching crystal structures.
I conducted the following search:
- Any electron donating group as a ring substituent, defined by any of the elements N, O, F, S, Cl, Br.
- A distance from the H of an OH fragment (as a hydrogen bonder to the aryl ring) to the ortho position relative to the electron donating group.
- A similar distance to the meta position.
- The |torsion angle| between the aryl plane and the C…H axis to be constrained to 90° ± 20.
- Restricting the H…C contact distance to the van der Waals sum of the radii -0.3Å (to capture only the stronger interactions)
- The usual crystallographic requirements of R < 0.1, no disorder, no errors and normalised H positions.
The result of such a search is seen below. The red line indicates those hits where the distance from the H to the ortho and meta positions is equal. In the top left triangle, the distance to ortho is shorter than to meta (and the converse in the bottom right triangle). You can see that both the red hot-spot and indeed the majority of the structures conform to ortho direction (of π-facial ) hydrogen bonding.
Here is a little calculation, optimising the position that HBr adopts with respect to bromobenzene. You can see that the distance discrimination towards ortho is ~ 0.17Å, a very similar value to the “hot-spot” in the diagram above.
This little search of course has hardly scratched the surface of what could be done. Changing eg the OH acceptor to other electronegative groups. Restricting the wide span of N, O, F, S, Cl, Br. Probing rings bearing two substituents. What of the minority of points in the bottom right triangle; are they true exceptions or does each have extenuating circumstances? Why do many points actually lie on the diagonal? Can one correlate the distances with the substituent? Is there a difference between intra and intermolecular H-bonds? What of electron withdrawing groups?
The above search took perhaps 20 minutes to define and optimise, and it gives a good statistical overview of this age-old effect. It is something every new student of organic chemistry can try for themselves! If you run an introductory course in organic aromatic chemistry, or indeed a laboratory, try to see what your students come up with!
References
- H.E. Armstrong, "XXVIII.—An explanation of the laws which govern substitution in the case of benzenoid compounds", J. Chem. Soc., Trans., vol. 51, pp. 258-268, 1887. https://doi.org/10.1039/ct8875100258
Tags:above search, Aromatic compounds, aromaticity, Birch reduction, Chemistry, electron donating, Electrophile, Electrophilic aromatic substitution, Ether, Functional groups, little search, Organic chemistry, Physical organic chemistry, Substitution reactions
Posted in Chemical IT, crystal_structure_mining | 1 Comment »
