Posts Tagged ‘acetic acid’

The “White City Trio” – The formation of an amide from an acid and an amine in non-polar solution (updated).

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).

Species

(FAIR Data DOI 10.14469/hpc/4598)

ΔG298 (ΔG298‡)

kcal/mol

Structure
Ionic reactants -649.737562♥ (0.0)
TS1 (N-C bond formation via acid PT) -649.702436 (22.0)
TS1 (N-C bond formation via amine PT), the “White City” -649.702307 (22.1)
TI1 from TS1 -649.709938 (17.3)
TS2 (PT from N to O via acid PT) -649.713027 (15.4)
TS2 (PT from N to O via amine PT), the “White City” -649.706042
TI2 from TS2 -649.711481 (16.4)
TS3 (O-C bond cleavage via amine PT), the “White City” -649.691918 (28.6) [30.5]‡
TS3 (O-C bond cleavage via acid PT) -649.689910 (29.9)
Non-ionic product from TS3 -649.732417 (+3.2)
Ionic product after PT -649.741246 (-2.3)

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.

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The "White City Trio" – The formation of an amide from an acid and an amine in non-polar solution (updated).

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).

Species

(FAIR Data DOI 10.14469/hpc/4598)

ΔG298 (ΔG298‡)

kcal/mol

Structure
Ionic reactants -649.737562♥ (0.0)
TS1 (N-C bond formation via acid PT) -649.702436 (22.0)
TS1 (N-C bond formation via amine PT), the “White City” -649.702307 (22.1)
TI1 from TS1 -649.709938 (17.3)
TS2 (PT from N to O via acid PT) -649.713027 (15.4)
TS2 (PT from N to O via amine PT), the “White City” -649.706042
TI2 from TS2 -649.711481 (16.4)
TS3 (O-C bond cleavage via amine PT), the “White City” -649.691918 (28.6) [30.5]‡
TS3 (O-C bond cleavage via acid PT) -649.689910 (29.9)
Non-ionic product from TS3 -649.732417 (+3.2)
Ionic product after PT -649.741246 (-2.3)

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.

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The mechanism of ester hydrolysis via alkyl oxygen cleavage under a quantum microscope

Tuesday, April 2nd, 2013

My previous dissection of the mechanism for ester hydrolysis dealt with the acyl-oxygen cleavage route (red bond). There is a much rarer[1] alternative: alkyl-oxygen cleavage (green bond) which I now place under the microscope.

alkyl-ester

Here, guanidine is used as a general acid/base, which results in a reasonable activation barrier for the hydrolysis (using pure water as the catalyst led to high barriers). What I will call the classical stepwise route is shown above, with charge-separated structures in abundance (particularly at the allyl group, where the possibility of forming a carbocation at this centre is central to the mechanism). My philosophy here is to allow quantum mechanics to decide whether to separate charge or not (in effect, only it is allowed decisions about where electrons are). So one can start with a concerted mechanism in which no formal charges are separated, and by subjecting them to wB97XD/6-311G(d,p)/SCRF=water calculation, decide where and if charges develop.

There are two distinct possibilities; hydrolysis with either retention or inversion of configuration at the alkyl group. The results for the transition states are shown below, with the analogous energy for acyl-oxygen cleavage shown for comparison.

Relative energies for hydrolysis of Alkyl acetate
R Acyl-oxygen Alkyl O,inversion Alkyl-O,retention
all H 0.0 15.3 42.5
Me 0.0 16.6 35.0
Me,Me 0.0 16.3 18.2
Me,Me,Me 0.0 16.4 (14.4)  ?

For R1=R2=R3=H and R1=Me,R2=R3=H proceeding with retention of configuration. The IRCs are as below, which reveal a “hidden intermediate” feature (visible as a dip in the gradient norm), which corresponds to a charge-separated zwitterionic intermediate immediately preceding the proton transfer. In other words, the non-charge-separated cyclic/concerted mechanism shown above is “interrupted” by charge separation in a hidden way during, and in an explicit way at the final stage, preferring finally to form the ionic ion-pair rather than neutral acetic acid and guanidine.

alkylg[2] alkylg
alkylMe[3] alkylMe
alkylMeG

For R1=R2=Me, R3=H, we have a change. The C-O bond lengths at the solvolysing methyl increase as the substitution at this carbon increases, e.g. 2.2Å (R=H) → 2.4Å (R1=Me) as the transition state becomes more carbocation like. With increasing carbocationic character, the acidity of the adjacent C-H group increases, until with R1=R2=Me, R3=H it has become acidic enough to be abstracted by any close-by base (in this instance, guanidine). Experimentally, the aqueous hydrolysis of t-butyl acetate is known to proceed with alkyl-oxygen cleavage[1]. In the computational model, the solvolysis mechanism has been intercepted by an elimination mechanism: the two potential surfaces under these circumstances are very close and they merge to ensure a different outcome of the reaction. You can see this effect below;

alkylG-Me2

Click for 3D.

The reaction barrier also drops as the degree of substitution at the migrating carbon increases. At time of writing, no TS had been located for R1=R2=R3 (? in table above) but as you can see the trend could easily take it below the energy for acyl oxygen hydrolysis.

A much lower energy route however is apparently available for the alkyl-oxygen solvolysis route. For R1=R2=R3=H, it proceeds much more favourably with inversion of configuration, an intramolecular Sn2 solvolysis in fact.

alkylg-inva alkylg-inva
alkylg-invg

That for R1=R2=R3 shows a qualitative difference, in resembling the mechanism for Sn1 solvolysis of t-butyl chloride in water. In this case the bond O-C bond labelled 2.3 is cleaving, whilst the C-O bond labelled 3.1 has not yet started to form; an apparently classical Sn1 solvolysis. But take a look at the two atoms labelled [1] and [2]; this C-H bond is also set up to be abstracted by an adjacent base (the carboxylate), and indeed an IRC shows the formation of butene (not solvolysis) to be the final outcome. 

Click for 3D.

Click for 3D.

Unlike the mechanism involving retention of configuration, the barrier for the inversion route does not change much as the substitution at the carbon increases, remaining above the acyl-oxygen solvolysis for even the t-butyl ester (R1=R2=R3=Me). 

To summarise what we might have learnt. Firstly, the mechanism of the apparently simple hydrolysis of alkyl esters of ethanoic (acetic) acid suddenly got much more complicated. It might seem that solvolysis of the O-alkyl bond can proceed with either inversion or retention of configuration at the alkyl carbon; if the latter then the barrier seems to decrease as the stabilisation of the carbocation at this carbon increases. But for both retention and inversion, the mechanistic pathway can easily be subverted by a different reaction involving the formation of an alkene.

One starts to suspect that the model I am using here to study this reaction may be either the wrong kind, or certainly incomplete. In the absence of any explicit water (merely a continuum model acting on its behalf), it seems more basic molecules bound in by hydrogen bonds (guanidine or carboxylate) can take over by acting as bases and abstracting hydrogens from a H-C bond adjacent to the carbocationic centre. In order to redirect the mechanism onto the solvolysis pathway, one probably needs to have a few more explicit water molecules hanging around (so to speak) so as to quickly intercept the forming carbocation, before it can release its proton to the base. In other words, one needs to set up a more statistical model, in which the probability of the desired outcome is in part determined by the probability of having a favourable molecule adjacent to the reacting centre. Who would have thought such a basic prototype for organic chemistry could be so tricky to pin down in a computational model! 

References

  1. C.A. Bunton, and J.L. Wood, "Tracer studies on ester hydrolysis. Part II. The acid hydrolysis of tert.-butyl acetate", Journal of the Chemical Society (Resumed), pp. 1522, 1955. https://doi.org/10.1039/jr9550001522
  2. H.S. Rzepa, "Gaussian Job Archive for C4H13N3O3", 2013. https://doi.org/10.6084/m9.figshare.663603
  3. H.S. Rzepa, "Gaussian Job Archive for C5H15N3O3", 2013. https://doi.org/10.6084/m9.figshare.663619

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The mechanism (in 4D) of the reaction between thionyl chloride and a carboxylic acid.

Friday, May 25th, 2012

If you have not previously visited, take a look at Nick Greeves’ ChemTube3D , an ever-expanding gallery of reactions and their mechanisms. The 3D is because all molecules are offered with X, Y and z coordinates. You also get arrow pushing‡ in 3D. Here, I argue that we should adopt Einstein, and go to the space-time continuum! By this, I mean one must also include the order in which things happen. To my knowledge, no compendium of (organic) reaction mechanisms incorporates this 4th dimension. My prelude to this post nicely illustrated this latter aspect. Here I continue with an exploration of the mechanism of forming an acyl chloride from a carboxylic acid using thionyl chloride. The mechanism shown at ChemTube3D is as below and will now be tested for its reasonableness using quantum mechanics.

Step (a, R=Me) is shown below (ωB97XD/6-311G(d,p)/SCRF=acetic acid);
  1. From IRC -6 to -2, the oxygen of the acid carbonyl approaches the sulfur. 
  2. IRC -2 then shows one chlorine to start move towards the OH, and the sulfur now adopts a “figure T” coordination.
  3. By IRC +2, the O…H…Cl angle has become almost linear, which is the optimum geometry for a proton transfer
  4. At IRC +3, the proton transfer from O to Cl is about half complete…
  5. A process largely complete by IRC +4.5
  6. Some residual activity takes place on the methyl group, which reorients itself with respect to the adjacent C-O bonds.
  7. The free energy barrier ΔG is 21.9 kcal/mol, which perhaps might be lowered if a solvation model including explicit hydrogen bonds were to be used.
Step (b) is related to the mechanism shown in the previous post, differing only in one aspect.₪ Step (c, R=Me) completes the reaction:
  1. The initial feature (IRC -2 to 0.0) is the cleavage of the C-O bond (1.862Å at the transition state)
  2. This point is 28.7 kcal higher in ΔG than the initial reactants, and is the highest energy point in the mechanism. As noted earlier, additional solvation-stabilisation involving discrete hydrogen bonds from e.g. acetic acid, is likely to lower this energy.
  3. This is followed (IRC +1.0 to +2.0) by a proton transfer from oxygen to chlorine.
Overall then, the scheme shown in ChemTube3D is reflected in reasonable energies calculated using quantum mechanics. The latter of course adds that fourth dimension, and gives us more insight into the order in which things happen. And I should add of course that simply because the mechanism shown here is reasonable, it does not exclude pathways which might be even lower in energy; it is indeed difficult to prove there is no other mechanism of (global) lower energy.

‡ I have discussed elsewhere the conventions used in arrow pushing. Nick uses the “American system” , whereas in this blog, I use a system I will call the Charles Rees method. I prefer this one, since it nicely maps onto more elaborate ways of identifying electron pairs in molecules, such as ELF and QTAIM, which themselves are based on quantum mechanics. Nick’s system differs mostly in the end-point for the arrows which he directs towards atoms whereas I direct them towards bonds. It might also be an interesting discussion point as to what criteria should be used to define three-dimensional arrow pushing; in effect the path that the arrow takes and what (pedagogic) meaning this might have.

₪ Following the initial proton transfer from Cl to oxygen, a very shallow minimum ion-pair is formed as a prelude to forming the C-Cl bond in a second step. This is because the additional oxygen present in a carboxylic acid stabilises the intermediate oxenium cation.

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Surprises (?) in the addition of HCl to a carbonyl group.

Thursday, May 24th, 2012

HCl reacting with a carbonyl compound (say formaldehyde) sounds pretty simple. But often the simpler a thing looks, the more subtle it is under the skin. And this little reaction is actually my prelude to the next post.

The mechanism is studied using ωB97XD/6-311G(d,p) with a simulated solvent (acetic acid) included (but not explicit solvent setting up any hydrogen bonds).

Transition state HCl + H2C=O. Click for 3D animation.

The transition state itself does not convey what is happening, largely because the transition state normal mode is mass-weighted. This leads to the heavier Cl not moving much, and the formaldehyde conducting a bee-dance like wag. For more detail, indeed insight, we need the intrinsic reaction coordinate (IRC):
  1. At IRC 4, the HCl starts by aligning itself into the plane of the formaldehyde, with the hydrogen targeting the in-plane lone pair on the carbonyl oxygen.
  2. At IRC 2.2, the hydrogen atom starts to transfer from the Cl to the O. As usual, a hydrogen transfer takes place very rapidly, and by IRC 1.7 the transfer is largely complete.
  3. At IRC 1.5, the chlorine, now shorn of its proton, starts to move out of the plane.
  4. At the transition state (IRC = 0.0) the chlorine is now inclined at an angle of about 45° with respect to the plane of the formaldehyde (which is still largely co-planar).
  5. Between IRC 0.0 and -2.0, the Cl…C bond starts to form, and the rotation goes to about 73°. It is held at this position because of an anomeric effect operating between one of the lone pairs on the oxygen atom, and the axis of the C-Cl σ* bond.
  6. The overall process is concerted, but quite asynchronous, in as much as the formation of the O…H bond distinctly precedes that of the C…Cl bond. These bonds form at a dihedral (torsional) angle of  73° with respect to each other and the need to align the two bonds in this manner means that they cannot form at the same rate!

Is this model a realistic one? Well, the missing component is hydrogen bonds. Between a solvent (this is being done by the way in acetic acid as simulated solvent) and the chlorine, which must assume a large measure of being actually a chloride anion, countered by the oxenium cation. It is possible that the reaction may actually therefore not be concerted, but it might stop at the half-way stage of an ion-pair before continuing its journey. The calculated barrier (~20 kcal/mol) is actually quite reasonable for a thermal reaction, but hydrogen-bond stabilisation might be expected to reduce this to what in effect would correspond to a very fast room-temperature reaction.

Well, HCl + H2C=O does not sound complicated. But you can trust this blog to take something simple and make it less so! 

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The oldest reaction mechanism: updated!

Tuesday, September 14th, 2010

Unravelling reaction mechanisms is thought to be a 20th century phenomenon, coincident more or less with the development of electronic theories of chemistry. Hence electronic arrow pushing as a term. But here I argue that the true origin of this immensely powerful technique in chemistry goes back to the 19th century. In 1890, Henry Armstrong proposed what amounts to close to the modern mechanism for the process we now know as aromatic electrophilic substitution [1]. Beyond doubt, he invented what is now known as the Wheland Intermediate (about 50 years before Wheland wrote about it, and hence I argue here it should really be called the Armstrong/Wheland intermediate). This is illustrated (in modern style) along the top row of the diagram.

The mechanism of aromatic electrophilic substitution

In 1887, Armstrong had tabulated the well known ortho/meta/para directing properties of substituents already on the ring towards this reaction[2]. He even offered an explanation, which is not entirely wrong, given that in 1890, the electron had not yet been discovered! That did not stop Armstrong, who invented an entity he called the affinity for the purpose of developing his theories (in this theory, benzene had an inner circle of six affinities, which had a tendency to resist disruption). Armstrong’s description of the properties of the affinity matches that of the (yet to be discovered) electron very closely! But that is enough of history. The mechanism shown above emerged in its present representation (and naming) during the heyday of physical organic chemistry between 1926 – 1940, and of course is an absolute staple of all text books on organic chemistry. But, sacrilege, is it correct? Could what is referred to as an intermediate instead be a transition state? (shown in the bottom pathway of the scheme).

Consider instead the following, in which X is replaced by an acetic acid motif;

Transition state alternative to the Wheland

The two steps, a bond formation between the benzene and E, and the proton abstraction from the benzene by X, are now synchronized into a single step, and the intermediate is now transformed into a transition state. Time to put this theory to the test. X is going to be made trifluoroacetate (R=CF3) and we are going to test it with E= NO+ and F+ (yes, trifluoroacetyl hypofluorite is a known chemical, and it really does fluorinate1 aromatic compounds at -78C). Firstly, E= NO+. A B3LYP/6-311G(d,p) calculation[3]  run in a solvent simulated as dichloromethane, reveals the mid point to indeed be a transition state and NOT an intermediate![4].

Wheland as a transition state. Click image for animation

There is one crucial aspect to this transition state that Armstrong himself made a point of. In the Wheland intermediate proper, the aromaticity of the benzene ring must be disrupted. As a transition state, it need not be (at least not completely). Thus the two bonds labeled as a have calculated lengths of ~1.415Å, only slightly longer than the aromatic length, and certainly not single bonds as implied by the Wheland intermediate! Notice also the significant motion by the hydrogen, which implies the reaction would be subject to a kinetic isotope effect (this would normally be interpreted in terms of the second stage of the stepwise reaction shown along the top a being rate limiting, but this result shows this need not be so). Thus, if the structure is favourable, this veritable old mechanism can be redesigned to give a new, 21st century look to a 19th century staple! By the way, the free energy of activation for this reaction is calculated as ~22 kcal/mol, a perfectly viable thermal reaction. No doubt, by suitable design of the group X, this might be reduced.

Now on to E=F+[5]. This looks a little different. F+ is now a much more voracious electrophile than the nitrosonium cation, and it therefore jumps ahead of the second mechanistic step, with no motion of the hydrogen being involved at this stage (one might also imagine making X a better base to swing things the other way).

Transition state E=F+ leading to Wheland Intermediate. Click for  3D model.

Genuine Wheland intermediate for E=F+ Click for 3D model

Now a full blown Armstrong/Wheland intermediate does indeed form (10042/to-5174); an intimate ion pair if you will, even in the relatively non polar dichloromethane as modelled solvent. The structure  (shown above) is rather unexpected.  This reaction has ΔG† of ~5 kcal/mol,  which is significantly lower than for the E=NO+ system.

Chemistry is full of surprises, and it is always a wonder how a slightly different take on even the oldest of reactions can reveal something new.

Reference.

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p>1. Umemoto, T.; Mukono, T.. 1-Acylamido-2-fluoro-4-acylbenzenes. Jpn. Kokai Tokkyo Koho  (1986), Patent number JP61246156.

References

  1. "Proceedings of the Chemical Society, Vol. 6, No. 85", Proceedings of the Chemical Society (London), vol. 6, pp. 95, 1890. https://doi.org/10.1039/pl8900600095
  2. 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
  3. "C 8 H 6 F 3 N 1 O 3", 2010. http://doi.org/10042/to-5172
  4. S.R. Gwaltney, S.V. Rosokha, M. Head-Gordon, and J.K. Kochi, "Charge-Transfer Mechanism for Electrophilic Aromatic Nitration and Nitrosation via the Convergence of (ab Initio) Molecular-Orbital and Marcus−Hush Theories with Experiments", Journal of the American Chemical Society, vol. 125, pp. 3273-3283, 2003. https://doi.org/10.1021/ja021152s

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