Posts Tagged ‘organic chemist’

The atom and the molecule: A one-day symposium on 23 March, 2016 celebrating Gilbert N. Lewis.

Friday, December 11th, 2015

You might have noticed the occasional reference here to the upcoming centenary of the publication of Gilbert N. Lewis’ famous article entitled “The atom and the molecule“.[1] A symposium exploring his scientific impact and legacy will be held in London on March 23, 2016, exactly 70 years to the day since his death. A list of the speakers and their titles is shown below; there is no attendance fee, but you must register as per the instructions below.

Royal Society of Chemistry Historical Group Meeting on 23th March 2016, Burlington House, Piccadilly, London: The atom and the molecule: A symposium celebrating Gilbert N. Lewis.

  • Dr Patrick Coffey (Berkeley, USA): Does Personality Influence Scientific Credit? Simultaneous Priority Disputes: Lewis vs. Langmuir and Langmuir vs. Harkins
  • Professor Robin Hendry (Durham, UK): Lewis on Structure and the Chemical Bond
  • Professor Alan Dronsfield (UK): An organic chemist reflects on the Lewis two-electron bond
  • Dr Julia Contreras-García (UPMC, France): Do bonds need a name?
  • Professor Nick Greeves (Liverpool, UK): The influence of Lewis on organic chemistry teaching, textbooks and beyond
  • Professor Clark Landis (UWM, USA): Lewis and Lewis-like Structures in the Quantum Era
  • Professor Michael Mingos (Oxford, UK): The Inorganic dimension to Lewis and Kossel’s landmark contributions
  • Dr Patrick Coffey (Berkeley, USA): Lewis’ Life, Death, and Missing Nobel Prize

Prior registration is essential. Please email your name and address to Professor John Nicholson,  jwnicholson01 @ gmail.com

References

  1. G.N. Lewis, "THE ATOM AND THE MOLECULE.", Journal of the American Chemical Society, vol. 38, pp. 762-785, 1916. https://doi.org/10.1021/ja02261a002

Tags:, , , , , , , , , , , , , , , , , ,
Posted in Interesting chemistry | 1 Comment »

WATOC2014 Conference report. Emergent themes.

Thursday, October 9th, 2014

This second report highlights two “themes”, or common ideas that seem to emerge spontaneously from diversely different talks. Most conferences do have them.

The first is “embedding“, which in this context means treating different parts of a probably complex molecular system at different levels of theory. Thus Emily Carter in her plenary described how a periodic crystal treated by density functional theory, or DFT could have an embedded component in which the electronic structures are described instead by multi-reference correlated wave functions (CAS-PT2). She illustrated this by discussing what happens when a triplet state oxygen molecule approaches the surface of an aluminium crystal, and (mostly) dissociates into surface bound oxygen atoms with Al-O bonds. The spin state of the oxygen changes smoothly to an overall singlet, with a rapid transfer of charge at the saddle point in the potential energy surface. The numbered of embedded Al atoms had to be at least a cluster of 14 to reproduce the observed reaction barriers (DFT on its own gets a zero barrier!). This sort of study is important in understanding the details of what is happening in metal surface catalysis.

Arieh Warshel then addressed the same theme with his own talk entitled Multiscale Modeling of Complex Biological Systems and Processes. Here you got quantum embedding in a mechanical force field description of some very large molecules. This was a broad brush talk, but what I did get out of it was the concept of asymmetry in molecular systems. Whereas an organic chemist thinks of asymmetry as often relating to just a single chiral carbon centre in a molecule, nature operates on vaster scales. Thus the enzyme ATPase has a molecular axle or spindle, which rotates to assemble the phosphate groups one at a time. This spindle rotates asymmetrically, i.e. always in a specific direction, and Warshel attempts to describe the origins of this rotational asymmetry at a molecular level. Well, this is Nobel prize winning stuff! He followed this up with filaments that “walk” along surfaces in one (asymmetric) direction, first lifting up one point of attachment, and then re-attaching at a different point such that the filament develops a clear sense of direction in its walk. This of course is all done with molecular dynamics, and (I think) has its origins in subtle electrostatics.

Stefan Grimme in his plenary also described dynamic processes, this time those that happen in a mass spectrometer when a molecule is ionised by electron impact. Removal of an electron produces a complex set of ionised states, in which many different single bonds may be weakened due to this ionisation. He developed simplified  DFT (sDFT) methods that can be applied to molecular dynamics, and assembled a “black box” which predicts the expected fragmentations over a time scale of a ps or so. By sampling the trajectories, he estimated the intensities of the various positively charged species and overlaid this on the observed EI-MS. The agreement was often spectacular. A particularly interesting example was the fragmentation of taxol. Here, no molecular ion is found, only much lighter ions. The molecular dynamics shows that rather than consecutive single-bond fragmentations, you instead get multiple bonds more or less all fragmenting at the same time. Tougher was to reproduce rearrangements, such as the McLafferty. Here, the semi-empirical method OM2 was more successful. His work means you can just “dial-a-mass-spectrum” and he speculates whether getting a good fit with the observed spectrum could tell you subtle aspects of the gas-phase molecular species, what its tautomeric state might be or perhaps even its conformation. He also described large-scale (800+) atom simulations of electronic circular dichroism (ECD) spectra of organometallic systems. Octahedral complexes can be prepared in chiral form, and this theoretical ECD treatment allows determination of absolute configuration of these often non-crystalline systems. Here you often need to compute 1000 or more electronic states, and if you have ever tried such ECD simulations, you will know that this is a lot of states!

We had been expecting Stefan to talk about dispersion effects in molecules, another emerging theme. Instead lots of other people mentioned them. In my talk I showed how including a D3-dispersion correction could dramatically change the predicted enantioselectivity of a chiral aldol condensation.[1]

The above observations of course cannot be in the least representative; typical of a modern conference there are five parallel sessions and 400+ posters, and so it represents a highly personal and selective snapshot.

References

    Tags:, , , , , , , , , , ,
    Posted in Interesting chemistry, WATOC reports | 1 Comment »

    Henry Armstrong: almost an electronic theory of chemistry!

    Monday, November 7th, 2011

    Henry Armstrong studied at the Royal College of Chemistry from 1865-7 and spent his subsequent career as an organic chemist at the Central College of the Imperial college of Science and technology until he retired in 1912. He spent the rest of his long life railing against the state of modern chemistry, saving much of his vitriol against (inter alia) the absurdity of ions, electronic theory in chemistry, quantum mechanics and nuclear bombardment in physics. He snarled at Robinson’s and Ingold’s new invention (ca 1926-1930) of electronic arrow pushing with the put down “bent arrows never hit their marks“.1  He was dismissed as an “old fogy, stuck in a time warp about 1894.”1 So why on earth would I want to write about him? Read on…

    He did worthy (nowadays this could mean dull) chemistry on e.g. naphthalenes, but I want to focus on two articles from the period 1887-1890 (10.1039/CT8875100258  and 10.1039/PL8900600095). Let me set the scene by reminding of an earlier post showing the structure of a bis(stilbyl)ketone, dated 1921. The two aromatic groups (yes, they really are such) are drawn in the manner we would nowadays draw cyclohexane. This practice in fact continued in texts and articles for perhaps 30 more years! Not much sign of electronic accounting there then! And by a professor at Imperial College no less, where Armstrong had been.

    Aromatic molecule, circa 1921

    So when would you date the diagrams below? So called Clar2 representations, originating from the 1950s? The one on the bottom below cites Clar and dates from 2010, DOI: 10.3390/sym2031653, but the one above it comes from Armstrong’s 1890 article!

    Two representations of pyrene, 2010 and 1890.

    Clar representations are used to count electrons (as coming in six packs). But there is little doubt that Armstrong’s use of a “C” (or inner circle, which is exactly what it is) means six as well. The evidence I present below, taken from his 1887 article.

    Armstrongs six pack

    1. He counts the six carbons as having a total of 24 what he calls affinities (definition: An attraction or force between particles that causes them to combine), or four per carbon. Let us make life easy and equate affinity=electron (remember, the electron itself was not yet discovered or named!). He disposes of 12 affinities/electrons to form what we now call six carbon-carbon σ bonds, and a further six for the  six C-H bonds.
    2. He is left with exactly six affinities/electrons, which he presupposes to act upon each other, in the manner of resultants (the old term for vectors). In fact, he replaces these six vectors by a circle (the inner circle) in his second article of 1890.
    3. He invents delocalization in all but name when he states that any one atom has an influence on other atoms not contiguous to it in the ring (he really did have o/m/p directing influence in mind here).
    4. He compares the introduction of a substituent (R, which comes from the old name Radicle) perturbing the distribution of the affinity to how electric charges perturb each other. So, the affinity behaves as if it might have electrical (from which the name electron came of course) properties? And it might be described by a vector?
    5. Remember, this is a scientist who in later life did not believe in electronic theories of chemistry? Really? Well, again in 1890:

    Is this an affinity (=electronic) theory of chemistry?

    1. Here, he is refining his vector representation of affinities, saying that these vectors in effect define a circle, an inner circle no less. One that can be disrupted  (Robinson some 30 years later wrote of how the cycle of six electrons are able to form a group that resists disruption) when an additive compound is formed (his examples are all electrophiles, what we now call electrophilic addition) such that the remaining carbons become merely unsaturated. There seems little doubt he is describing what we now call a Wheland Intermediate.
    2. Is this really a man who did not believe in electronic theories of chemistry? What about that concluding paragraph then? The laws of substitution require a knowledge of the inner structure of (what we now call the aromatic) hydrocarbons?
    3. And that such speculations may suggest fresh lines of experimental inquiry? This all sounds very much like the modern use of quantum mechanics and its electronic eigenvectors to describe the probability distribution of electrons (remember, Armstrong did not approve of this either) to probe the inner structure of molecules and to suggest new experiments.

    We have a real mystery. Armstrong got so very close to a modern theory of chemistry. Was he asleep when Stoney named the electron around 1891 and Thomson discovered it in 1897? If only he had followed his own advice! Ah well, just as well he was ignored in the 20th century when he preached against it all.

    1. W. H. Brock, “The case of the Poisonous Socks”, chapter 20, RSC Publishing, 2011, 978-1-84973-324-3
    2. Clar, E. The Aromatic Sextet; Wiley: New York, NY, USA, 1972.

    Tags:, , , , , , , , , , , , , ,
    Posted in Historical | 3 Comments »

    The Cyclol Hypothesis for protein structure: castles in the air.

    Monday, April 4th, 2011

    Most scientific theories emerge slowly, over decades, but others emerge fully formed virtually overnight as it were (think  Einstein in 1905). A third category is the supernova type, burning brightly for a short while, but then vanishing (almost) without trace shortly thereafter. The structure of DNA (of which I have blogged elsewhere) belongs to the second class, whilst one the brightest (and now entirely forgotten) examples of the supernova type concerns the structure of proteins. In 1936, it must have seemed a sure bet that the first person to come up with a successful theory of the origins of the (non-random) relatively rigid structure of proteins would inevitably win a Nobel prize (and of course this did happen for that other biologically important system, DNA, some 17 years later). Compelling structures for larger molecules providing reliable atom-atom distances based on crystallography were still in the future in 1936, and so structural theories contained a fair element of speculation and hopefully inspired guesswork (much as cosmological theories appear to have nowadays!).

    Dorothy Wrinch was a mathematician who came up with just such a hypothesis for rigid protein structure, based in effect on elegance and symmetry, coupled with some knowledge of chemistry and crystallography[1]. She had noticed that the repeating polypeptide motif might be folded such that a cyclisation could occur to give what she termed a cyclol (an organic chemist would call this an aminol, and we would also now recognize it as a three-fold tetrahedral intermediate of the type involved in the hydrolysis of peptides). Wrinch proposed that this cyclisation could be repeated on a large scale to produce rigid scaffolds for proteins. The three-fold symmetric elegance of such motifs clearly appealed to this mathematician (the interesting symmetrical and conformational properties of the central cyclohexane-like ring were still to be fully recognised by anyone. Since Wrinch built many 3D models of her cyclols, one can but wonder how that central ring was represented, and whether its chair conformation was at all recognised. Another Nobel prize awaited the discoverer of this, Derek Barton).

    The Cyclol structure. Click for 3D.

    An immense controversy immediately broke out (not least because little direct spectroscopic evidence for the OH groups could be found). The story is rivetingly told by Patrick Coffey in his book Cathedrals of Science (ISBN 978-0-19-532134-0). Linus Pauling entered the fray in 1939[2], and one of the arguments he deployed was not so much symmetric elegance but thermodynamics (he also suggested hydrogen bonding and  S-S linkages for rigidifying proteins). The proposed cyclisation, he suggested, led to a very high energy species. Whilst Wrinch attempted to refute this[3], Pauling’s arguments won almost everyone over. Although Wrinch forlornly continued to promote her idea, last reviewing the topic as late as in 1963[4], crystallography was now producing cast iron data for protein structures. None have ever emerged with a cyclol motif, and this hypothesis is now firmly consigned to untaught history[5]. To this day, no examples of the tris(aminol) cyclol ring are to be found in the Cambridge small molecule crystal structure database either (although some related tetrahedral intermediates are known as crystalline species, see for example here, and they can be quite easily characterised in solution, see for example[6].

    When  I read the story, it struck me that modern theory could easily verify how valid Pauling’s thermodynamic argument was. I have picked (ala)6 as my model, and have calculated the relative free energy (ΔG298) of the following three isomers.

    1. An acyclic zwitterionic form of this hexapeptide, calculated with a SCRF reaction field for water to allow for the ionic nature (ωB97XD/6-31G(d,p)), reveals a proton transfer to a neutral system, with an energy of +7.3 kcal/mol

      Acyclic (ala)6, in zwitterionic form

    2. A cyclic neutral peptide, which results from elimination of water from 1, again calculated with a water reaction field (DOI: 10042/to-8219), revealing a relative free energy of +0.0 kcal/mol

      Cyclic (ala)6

    3. The cyclic isomer 3 resulting from further cyclisation of 2 (DOI: 10042/to-8222) with a relative free energy of +69.0 kcal/mol

      Cyclol model for (ala)6.

    From this, it appears that model 3 is ~69 kcal/mol less stable than the cyclic peptide 2, or 11.6 kcal/mol per amino acid residue. Pauling’s thermodynamic arguments suggested a value of ~28 kcal/mol (a value which Wrinch disputed as unreliable). So, in one sense, the above calculation is closer to Wrinch than to Pauling! In another, it still means Wrinch was wrong!! It is worth speculating why Pauling’s estimate is out. The cyclol 3 exhibits anomeric stabilizations, which of course were unknown in Pauling’s time. Both 2 and 3 exhibit attractive, but different, van der Waals attractions which contribute to their stabilities. And Pauling took no account of any entropy differences between 2 and 3. In retrospect,  3 was simply too rigid to allow most enzyme catalysis models to function, as we recognise them nowadays.

    You might ask why I have revived a long forgotten theory as the topic of this post. Well, I think it is always worth revisiting the past, and re-examining old assumptions. When we do so, we find that Wrinch did not miss by as much as her detractors perhaps implied. With a little more luck, she might have gotten it right. Science is a bit like that, you need a dose of luck sometimes!

    References

    1. "The cyclol hypothesis and the “globular” proteins", Proceedings of the Royal Society of London. Series A - Mathematical and Physical Sciences, vol. 161, pp. 505-524, 1937. https://doi.org/10.1098/rspa.1937.0159
    2. L. Pauling, and C. Niemann, "The Structure of Proteins", Journal of the American Chemical Society, vol. 61, pp. 1860-1867, 1939. https://doi.org/10.1021/ja01876a065
    3. D.M. Wrinch, "The Geometrical Attack on Protein Structure", Journal of the American Chemical Society, vol. 63, pp. 330-333, 1941. https://doi.org/10.1021/ja01847a004
    4. D. WRINCH, "Recent Advances in Cyclol Chemistry", Nature, vol. 199, pp. 564-566, 1963. https://doi.org/10.1038/199564a0
    5. C. Tanford, "How protein chemists learned about the hydrophobic factor", Protein Science, vol. 6, pp. 1358-1366, 1997. https://doi.org/10.1002/pro.5560060627
    6. H.S. Rzepa, A.M. Lobo, M.M. Marques, and S. Prabhakar, "Characterizing a tetrahedral intermediate in an acyl transfer reaction: An undergraduate 1H NMR demonstration", Journal of Chemical Education, vol. 64, pp. 725, 1987. https://doi.org/10.1021/ed064p725

    Tags:, , , , , , , , , , , ,
    Posted in Interesting chemistry | 2 Comments »

    Semantically rich molecules

    Sunday, May 2nd, 2010

    Peter Murray-Rust in his blog asks for examples of the Scientific Semantic Web, a topic we have both been banging on about for ten years or more (DOI: 10.1021/ci000406v). What we are seeking of course is an example of how scientific connections have been made using inference logic from semantically rich statements to be found on the Web (ideally connections that might not have previously been spotted by humans, and lie overlooked and unloved in the scientific literature). Its a tough cookie, and I look forward to the examples that Peter identifies. Meanwhile, I thought I might share here a semantically rich molecule. OK, I identified this as such not by using the Web, but as someone who is in the process of delivering an undergraduate lecture course on the topic of conformational analysis. This course takes the form of presenting a set of rules or principles which relate to the conformations of molecules, and which themselves derive from quantum mechanics, and then illustrating them with selected annotated examples. To do this, a great many semantic connections have to be made, and in the current state of play, only a human can really hope to make most of these. We really look to the semantic web as it currently is to perhaps spot a few connections that might have been overlooked in this process. So, below is a molecule, and I have made a few semantic connections for it (but have not actually fully formalised them in this blog; that is a different topic I might return to at some time). I feel in my bones that more connections could be made, and offer the molecule here as the fuse!

    Two chair conformations of the molecule DULSAE. Click here for 3D. Note the (attractive) short H...H contacts.

    To list all the likely semantics that a chemist would perceive in the graphic above would take far too long (by the time one would have finished, a text book would have been written). So here is a very very short summary in the context of conformational analysis.

    1. The molecule has a six membered ring as its backbone
    2. which can adopt two possible chair conformations
    3. which can interconvert by exchanging the axial and equatorial group pair for each of the four carbon atoms in the ring.
    4. An organic chemist will immediately notice a very unusual group, Fe(CO)2Cp, which itself is a semantic goldmine,
    5. but for the purposes here we will regard merely as a C-Fe bond!

    The (semantic) question to be posed is “which of the two conformations shown above is the most stable“? That too of course has an abundance of implicit semantics, but most human chemists will probably know that this refers to asking which of the two geometries represents the lowest thermodynamic free energy (and we leave aside the issue of what medium the molecule is in, i.e. solid, solution or gas). A far trickier question is “why”?

    So to (some interim) answers. Well, a ωB97XD/6-311G(d) calculation (wow, think of what is implied in that concise notation) predicts conformation (a) to be more stable by 2.3 kcal/mol (2.1 in ΔG, see DOI: 10042/to-4911). Now to the why. What connections would someone well versed in conformation analysis spot?

    1. The molecule has two methyl groups on adjacent atoms. They may prefer to be di-axial rather than di-equatorial to avoid excessive steric repulsions (whatever we mean by that!). That might prefer (b).
    2. The molecule has one carbon with both a cyano and an ether linkage. Well, that is susceptible to an anomeric effect (although, as I pointed out in an earlier post here, this connection has in fact often NOT been made in the literature). Only in conformation (a) is one of the oxygen lone pairs aligned anti-periplanar to the axis of the C-CN bond. The reasons why this is important are outlined in my Lecture course.
    3. Having spotted the last, the human might ask whether there is any possibility of an anomeric effect between an oxygen lone pair and the axis of the C-Fe bond? Well, I rather think that not a single human ever has asked that question! (I cannot know that of course, and perhaps someone has speculated upon this in the literature; this is where a full semantic web would help. That question could be posed of it! The reason  I suspect the connection might not have been made is that the anomeric effect is the domain of the organic chemistry, and  C-Fe bonds are those of the organometallic chemist. They do tend to see the chemical world rather differently, these two groups of chemists). If there was such an effect, it would favour (a).
    4. Then we have an X-C-C-Y motif. Depending on the nature of X and Y, the molecule might actually prefer a gauche conformation, i.e the dihedral angle XCCY would be around 60°. There are several such motifs one can detect; X=Y=O (twice). It might be that other permutations such as X=CN, Y=Fe(CO)2Cp, favour anti-periplanar. There are other permutations whose orientational preference may not even be recorded (in text books). Suddenly its gotten complicated!
    5. There are a number of short (~2.4Å) H…H contacts
    6. We are starting to understand that to unravel the conformation of this molecule, one may have to identify quite a number of different “rules”, and then to quantify each, and add up the numbers to get the final result. That energy of 2.3 kcal/mol may be composed of the result of applying quite a number of different rules. Hence the title of this post, a semantically rich molecule!

    Well, I will leave it here for this post, without giving answers to the six points listed above, or really answering my main question posed above. That would make the post too complex (but I will follow this up!). I do want to end by planting the idea that answering this question involves making a great many chemical connections about the properties of this molecule, and then identifying quantitative ways (algorithms) in which an answer can be formulated. The molecule above is presented as a challenge for the Semantic Web to address!

    Tags:, , , , , , , , , , , , , ,
    Posted in Chemical IT, General, Interesting chemistry | 2 Comments »