Posts Tagged ‘Acid’
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, 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 »
Friday, April 8th, 2016
Previously, I looked at models of how ammonia could be protonated by water to form ammonium hydroxide. The energetic outcome of my model matched the known equilbrium in water as favouring the unprotonated form (pKb ~4.75). I add here two amines for which R=Me3Si and R=CN. The idea is that the first will assist nitrogen protonation by stabilising the positive centre and the second will act in the opposite sense; an exploration if you like of how one might go about computationally designing a non-steric superbasic amine that becomes predominantly protonated when exposed to water (pKb <1)† and is thus more basic than hydroxide anion in this medium.
Before reporting any calculations, let us see what the CSD (Cambridge structure database) might contain. The search query is simple, a 3-coordinate amine forming a 4-coordinate quaternary nitrogen† with one N-H and a positive (formal) charge on the N, and a 1-coordinate oxygen with one O-H and a negative charge on the O. With the constraints R < 10%, no disorder and no errors, one gets as many as 15 hits,[1] several of which also apparently contain separate water molecules in the crystal. A warning bell (perhaps several) sounds, since if R < 5%, the number of hits drops to just 2; these are clearly difficult structures to refine!‡ So there is some tantalising evidence that in the solid state at least, the quaternary ammonium group (with at least one N-H), water and a hydroxide anion might be capable of co-existence. As noted below† some fascinating 2-coordinate amines have also been reported as having superbasic properties.
R=CN: the well known compound cyanamide is known to act only as an acid and its basic properties are never quoted. Shown below is the reaction path for transfer of a proton from water to the amine using an 8-water model (n=8) in which two bridges can serve to help stabilize any ionic form. The energy required to do so however is at least 24 kcal/mol (ωB97XD/Def2-TZVPPD/SCRF=water) which indicates that no protonated amine is formed. This can be attributed to the electron withdrawing cyano group strongly destablising any adjacent positive ammonium centre and thus effectively completely inhibiting its formation.
R=Me3Si: this too is already known[2],[3] but only in the presence of the non-coordinating counter-anion B(C6F5)4 crystallised from non-protic solution. An ionised form can now be located using the model above. This has the structure shown below; note the very short hydrogen bonds associated with the hydroxide anion and the possibility of forming only two water bridges across the ion-pair. The relative free energy of the ion-pair (table below) shows it to be if anything less basic than ammonia.
NBO (natural bond orbital) analysis might here be a useful metric of basicity. Hence Me3SiNH2…H2O suggests that donation from the N lone pair into an antiperiplanar Si-C bond is quite large (E(2) = 11.9 kcal/mol), although alternative donation by nitrogen into the H-O σ* bond of the water is much higher (33.4 kcal/mol).
Perhaps the basicity of simple amines is related to their ability to form stabilizing water bridges across the ion-pair? With trimethylsilyl substituents, this feature (and hence the basicity) is partially or even fully suppressed as in e.g. tris(trimethylsilyl)amine.The pKb of the latter appears to be unreported[8] but it does seem to be only weakly basic and "inert to H2O",[9] a property attributed instead to multiple character in the Si-N bonds.
I will in a future post look at the alternative class of phosphazenium amines which do manage to achieve superbasicity.[10]
†A phosphazenium 3-coordinate amine[11] was in 1991 claimed to be the strongest metal-free neutral base. This has now been superceded by combining this base motif with that of a sterically operating proton sponge.[12],[10] I will report the computational modelling of these systems in a later post.
‡One of the structures identified with R<10% is UBEJIU[13] and which is worth showing below. Note the apparent close contact of the type N-H…H-O (1.416-1.463Å) rather than the expected N-H…OH. If correct (this feature is not mentioned in the article itself) it would be classified as a dihydrogen bond, a type normally only found in situations such as B-H…H-N. There are a number of other inconsistencies which must be resolved if this structure is to stand as correct.
References
- H. Rzepa, "Substituted ammonium hydroxides", 2016. https://doi.org/10.14469/hpc/361
- Y. Sarazin, J.A. Wright, and M. Bochmann, "Synthesis and crystal structure of [C6H5Hg(H2NSiMe3)][H2N{B(C6F5)3}2], a phenyl–mercury(II) cation stabilised by a non-coordinating counter-anion", Journal of Organometallic Chemistry, vol. 691, pp. 5680-5687, 2006. https://doi.org/10.1016/j.jorganchem.2006.09.021
- Sarazin, Y.., Wright, J.A.., and Bochmann, M.., "CCDC 608250: Experimental Crystal Structure Determination", 2007. https://doi.org/10.5517/ccndxzx
- H.S. Rzepa, and H.S. Rzepa, "H21NO9", 2016. https://doi.org/10.14469/ch/191946
- H.S. Rzepa, and H.S. Rzepa, "C 3 H 29 N 1 O 9 Si 1", 2016. https://doi.org/10.14469/ch/191987
- H.S. Rzepa, and H.S. Rzepa, "C 3 H 29 N 1 O 9 Si 1", 2016. https://doi.org/10.14469/ch/191982
- H.S. Rzepa, "CH20N2O9", 2016. https://doi.org/10.14469/ch/191983
- E.W. Abel, D.A. Armitage, and G.R. Willey, "Relative base strengths of some organosilicon amines", Transactions of the Faraday Society, vol. 60, pp. 1257, 1964. https://doi.org/10.1039/tf9646001257
- J. Goubeau, and J. Jimenéz‐Barberá, "Tris‐(trimethylsilyl)‐amin", Zeitschrift für anorganische und allgemeine Chemie, vol. 303, pp. 217-226, 1960. https://doi.org/10.1002/zaac.19603030502
- Kögel, Julius F.., Oelkers, Benjamin., Kovačević, Borislav., and Sundermeyer, Jörg., "CCDC 1002088: Experimental Crystal Structure Determination", 2014. https://doi.org/10.5517/cc12mrfw
- R. Schwesinger, and H. Schlemper, "Peralkylated Polyaminophosphazenes— Extremely Strong, Neutral Nitrogen Bases", Angewandte Chemie International Edition in English, vol. 26, pp. 1167-1169, 1987. https://doi.org/10.1002/anie.198711671
- J.F. Kögel, B. Oelkers, B. Kovačević, and J. Sundermeyer, "A New Synthetic Pathway to the Second and Third Generation of Superbasic Bisphosphazene Proton Sponges: The Run for the Best Chelating Ligand for a Proton", Journal of the American Chemical Society, vol. 135, pp. 17768-17774, 2013. https://doi.org/10.1021/ja409760z
- P. Vianello, A. Albinati, G.A. Pinna, A. Lavecchia, L. Marinelli, P.A. Borea, S. Gessi, P. Fadda, S. Tronci, and G. Cignarella, "Synthesis, Molecular Modeling, and Opioid Receptor Affinity of 9,10-Diazatricyclo[4.2.1.1<sup>2,5</sup>]decanes and 2,7-Diazatricyclo[4.4.0.0<sup>3,8</sup>]decanes Structurally Related to 3,8-Diazabicyclo[3.2.1]octanes", Journal of Medicinal Chemistry, vol. 43, pp. 2115-2123, 2000. https://doi.org/10.1021/jm991140q
Tags:Acid, Acid dissociation constant, Amide, Amine, Ammonia, Ammonium, Bases, City: Cambridge, energy, from non-protic solution, Functional groups, Hydrogen bond, Hydroxide, Lone pair, metal, Nitrile, relative free energy, search query
Posted in General, Interesting chemistry | 2 Comments »
Sunday, January 10th, 2016
Earlier I explored models for the heteroaromatic electrophilic protiodecarboxylation of an 3-substituted indole, focusing on the role of water as the proton transfer and delivery agent. Next, came models for both water and the general base catalysed ionization of indolinones. Here I explore general acid catalysis by evaluating the properties of two possible models for decarboxylation of 3-indole carboxylic acid, one involving proton transfer (PT) from neutral water in the presence of covalent un-ionized HCl (1) and one with PT from a protonated water resulting from ionised HCl (2).
The original study[1] noted that the rate of decarboxylation fitted well to the kinetic expression: rate = {a + b[L3O+]/(1 + c[L3O+])}[indole], where L can be H or D. Experimentally, [L3O+] is controlled by adding a strong general acid such as HCl, which when the appropriate number of water molecules are added[2] fully ionizes to H3O+.OH–. Now for B3LYP+D3/Def2-TZVPD/SCRF=water calculations:
- Model 1 takes the pure water model and adds HCl (blue above) via hydrogen bonding to the H2O that is transferring the proton to the indole ring. Three water molecules are hydrogen bonding to the carboxylate oxygens to create a bicyclic network in which a ring of either 8 or 10 atoms can act as the proton relay structure. The question now arises whether the proton relay takes the longer (red) route or the slightly shorter green route.
- Isomeric model 2 uses H3O+ for proton transfer, with an adjacent Cl– to complete the ion-pair.
‡Reactant as a non-ionised covalent HCl. †reactant as an isomeric ionized H3O+.Cl– beng 2.0 kcal/mol higher in energ within this solvation model.
- An IRC for Model 1 shows that the proton relay takes the red path, whereas without the HCl the green path is followed.
The transition state free energy however is ..
- 10.6‡ or 8.6† kcal/mol higher than model 2 (click on the image below to load a 3D model). The general acid catalysed model is therefore preferred. The difference in free energy between the two models corresponds to a rate acceleration of >106, which is indeed similar to that observed[1].
The clincher comes with calculation[3] of the kinetic isotope effects (KIE). For general acid catalysis, they were measured as kH/kD ~2.5.[1]
- For model 1, using an un-ionised reactant and un-ionised transition state, the calculated KIE is 5.69 (very similar to that calculated for the water catalysed reaction, 5.66) but not a good fit to experiment.
- For model 2, using the same un-ionised reactant but an ionised transition state, KIE = 2.04, a much better fit.
- For model 2, using ionised reactant AND transition state, KIE = 2.45, an even better fit to experiment.
So we now have a model for the general acid catalysed decarboxylation of a 3-indole carboxylate which agrees with both the kinetic behaviours and the isotope effects measured for this reaction. Since the barrier is a relatively large one, proton tunnelling may play a lesser role in this interpretation, and the stage is set to use this model to e.g. explore how isotope effects are indeed influenced by tuning the reactivity using ring substitutents, the original purpose of my researches all those years ago. Perhaps the catch phrase I’ve started so I’ll start is now more apposite.
References
- B.C. Challis, and H.S. Rzepa, "Heteroaromatic hydrogen exchange reactions. Part 9. Acid catalysed decarboxylation of indole-3-carboxylic acids", Journal of the Chemical Society, Perkin Transactions 2, pp. 281, 1977. https://doi.org/10.1039/p29770000281
- A. Vargas‐Caamal, J.L. Cabellos, F. Ortiz‐Chi, H.S. Rzepa, A. Restrepo, and G. Merino, "How Many Water Molecules Does it Take to Dissociate HCl?", Chemistry – A European Journal, vol. 22, pp. 2812-2818, 2016. https://doi.org/10.1002/chem.201504016
- H. Rzepa, "Ionic model for general acid catalysed decarboxylation", 2016. https://doi.org/10.14469/hpc/204
- H.S. Rzepa, "C 9 H 16 Cl 1 N 1 O 6", 2016. https://doi.org/10.14469/ch/191792
- H.S. Rzepa, "C 9 H 16 Cl 1 N 1 O 6", 2016. https://doi.org/10.14469/ch/191795
- H.S. Rzepa, "C 9 H 16 Cl 1 N 1 O 6", 2016. https://doi.org/10.14469/ch/191794
- H.S. Rzepa, "C9H16ClNO6", 2016. https://doi.org/10.14469/ch/191767
- H.S. Rzepa, "C 9 H 16 Cl 1 N 1 O 6", 2016. https://doi.org/10.14469/ch/191790
Tags:Acid, Acids, bicyclic network, carboxylic acid, free energy, Functional groups, Hydrogen bond, Indole, transition state free energy
Posted in Interesting chemistry | 1 Comment »
