Posts Tagged ‘Amide’
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 »
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 »
Saturday, September 5th, 2015
The previous post explored the structural features of amides. Here I compare the analysis with that for the closely related thioamides.
Here is the torsional analysis around the C-N bond. The “diff” (difference) is that almost all the hits are concentrated into angles of 0° or 180°; the twist about the C-N bond from co-planarity is much less if S is present. This is normally explained in terms of Spπ-Cpπ overlaps being less favourable than Opπ-Cpπ ones owing to the mismatch in the size of the atomic orbital for S and C. Hence the resonance which reduces the C=S double bond character in favour of greater C=N character is enhanced compared to O.
A consequence is that the nitrogen atom is less easily deformed from planarity in a thioamide. Notice also that at the hotspot, the C=N distance is ~1.32Å compared to 1.34Å for a regular amide.
This emerges from the plot below as well; the range of values for the C-N bond is reduced compared to amides, but the diagonal trend that as the C=N bond gets longer so the C-S gets shorter is still seen.
All these trends are described qualitatively in most text books of organic chemistry, but one never sees statistical evidence for them. And it truly only takes 5-10 minutes to produce.
Tags:Amide, Functional groups, Thioamide
Posted in Chemical IT, crystal_structure_mining | No Comments »
Saturday, September 5th, 2015
The previous post explored the structural features of amides. Here I compare the analysis with that for the closely related thioamides.
Here is the torsional analysis around the C-N bond. The “diff” (difference) is that almost all the hits are concentrated into angles of 0° or 180°; the twist about the C-N bond from co-planarity is much less if S is present. This is normally explained in terms of Spπ-Cpπ overlaps being less favourable than Opπ-Cpπ ones owing to the mismatch in the size of the atomic orbital for S and C. Hence the resonance which reduces the C=S double bond character in favour of greater C=N character is enhanced compared to O.
A consequence is that the nitrogen atom is less easily deformed from planarity in a thioamide. Notice also that at the hotspot, the C=N distance is ~1.32Å compared to 1.34Å for a regular amide.
This emerges from the plot below as well; the range of values for the C-N bond is reduced compared to amides, but the diagonal trend that as the C=N bond gets longer so the C-S gets shorter is still seen.
All these trends are described qualitatively in most text books of organic chemistry, but one never sees statistical evidence for them. And it truly only takes 5-10 minutes to produce.
Tags:Amide, Functional groups, Thioamide
Posted in Chemical IT, crystal_structure_mining | No Comments »
Saturday, September 5th, 2015
The π-resonance in amides famously helped Pauling to his proposal of a helical structure for proteins. Here I explore some geometric properties of amides related to the C-N bond and the torsions about it.
The key aspect of amides is that a lone pair of electrons on the nitrogen can conjugate with the C=O carbonyl only if the lone pair orbital is parallel to the C-O π-system. We can define this with the O=C-N-R torsion angle (and equate 0 or 180° with the p-orbitals being parallel). In the above definition, each R can be either 4-coordinate C (to avoid alternative conjugations) or H and the C-N bond is specified as being cyclic. As usual the R-factor is < 5%, no errors, no disorder.
First, the C-N torsion, which adopts values of either 0 or 180°. Notice that whilst the anti R-group shows no more than about 20° deviation from 180°, it does have a small tail tending towards longer C-N distances of >1.4Å. The hotspot is for the syn R-group. Here there is a strong trend that as the dihedral deviates from 0° the C-N bond very clearly elongates. As the π-π overlap decreases, the bond elongates from the hot spot value of ~1.34Å to 1.41Å at 50°. The greater propensity of the syn-R to twist may be because it incurs more steric hindrance or perhaps because we have defined the C-N bond to be part of a cycle.
Next, we plot the C-N distance against the torsion R-N-C-R’, which defines how planar the nitrogen is. A value of 180° is planar and the hot-spot is here. But as the planarity decreases down to almost tetrahedral (110°) the C-N bond elongates to 1.41Å. Notice one rather intriguing aspect; from 180° to 160° or so, there is little response from the C-N bond, but the elongation really accelerates from 140° to 110°. A little twisting hardly affects the π-π overlap, but it really starts to matter for twists of >50°.
Finally a plot of the C-N vs the C-O distances. As the C-N increases, the C-O contracts, this being a nice summary of the π resonance in amides.
We have not seen any surprises, but this statistical exploration of crystal structures at least puts some numbers on the changes in bond lengths as a result of conjugative resonance.
Tags:Amide, chemical bonding, Conjugated system, Physical organic chemistry, Resonance
Posted in Chemical IT, crystal_structure_mining | 1 Comment »
