Tag Archives: aromaticity

Ring currents ride again

One of the most impressive pieces of evidence (to me at least) that we really understand what electrons are doing in organic molecules are the ring currents. Recall that the pi electrons in benzene are delocalized above and below the planar ring determined by the 6 carbon atoms.

How do we know this? When a magnetic field is applied the electrons in the ring cloud circulate to oppose the field. So what? Well if you can place a C – H bond above the ring, the induced current will shield it. Such molecules are known, and the new edition of Clayden (p. 278) shows the NMR spectra showing [ 7 ] paracyclophane which is benzene with 7 CH2’s linked to the 1 and 4 positions of benzene, so that the hydrogens of the 4th CH2 is directly over the ring (7 CH2’s aren’t long enough for it to be anywhere else). Similarly, [ 18 ] Annulene has 6 hydrogens inside the armoatic ring — and these hydrogens are even more deshielded. Interestingly building larger and larger annulenes, as shown that aromaticity decreases with increasing size, vanishing for systems with more than 30 pi electrons (diameter 13 Angstroms), probably because planarity of the carbons becomes less and less possible, breaking up the cloud.

This brings us to Nature vol. 541 pp. 200 – 203 ’17 which describes a remarkable molecule with 6 porphyins in a ring hooked together by diyne linkers. The diameter of the circle is 24 Angstroms. Benzene and [ 18 ] Annulene have all the carbons in a plane, but the picture of the molecule given in the paper does not. Each of the porphyrins is planar of course, but each plane is tangent to the circle of porphyrins.

Also discussed is the fact that ‘anti-aromatic’ ring currents exist, in which they circulate to enhance rather than diminish the imposed magnetic field. The molecule can be switched between the aromatic and anti-aromatic states by its oxidation level. When it has 78 electrons ( 18 * 4 ) + 2 in the ring (with a charge of + 6) it is aromatic. When it has 80 elections with a + 4 charge it is anti-aromatic — further confirmation of the Huckel rule (as if it was needed).

On a historical note reference #27 is to a paper of Marty Gouterman in 1961, who was teaching grad students in chemistry in the spring of 1961. He was an excellent teacher. Here he is at the University of Washington — http://faculty.washington.edu/goutermn/

Breaking benzene

Industrially to break benzene aromaticity in order to add an alkyl group using the Friedel Crafts reaction requires fairly hairy conditions — http://www.chemguide.co.uk/organicprops/arenes/fc.html e.g. pressure to keep everything liquid and temperatures of 130 – 160 Centigrade.

A remarkable paper [ Nature vol. 512 pp. 413 – 415 ’14 ] uses a Titanium hydride catalyst and mild conditions (22 C — room temperature) for little over a day to form a titanium methylcyclopentenyl complex from benzene (which could be isolated) and studied spectroscopically.

The catalyst itself is rather beautiful. 3 titaniums, 6 hydrides and 3 C5Me4SiMe3 groups.

Benzene is the aromaticity workhorse of introductory organic chemistry. If you hydrogenate cyclohexene 120 kiloJoules is given off. Hydrogenating benzene should give off 360 kiloJoules, but because of aromatic stabilization only 208 is given off — implying that aromaticity lowers the energy of benzene by 152 kiloJoules. Clayden uses kiloJoules. I’m used to kiloCalories. To get them divide kiloJoules by 4.19.

What other magic does transition metal catalysis have in store?

Aromatic rings are planar in proteins aren’t they? More trouble for computational chemistry

Every organic chemistry book worth its salt has a diagram of the heats of hydrogenation of Benzene (the new Clayden has it on p. 158).  Adding H2 across a double bond releases energy, because saturated hydrocarbons have a lower energy than alkenes.  However the heat of hydrogenation of benzene is some 208 kiloJoules/mole, which is considerably less than 3 times the heat of hydrogenation of cyclohexene (3 * 120 kiloJoules/mole).  Then we’re off for a romp through the planarity of benzene allowing the p orbitals to overlap, the Huckel rules etc. etc.  It’s why benzene (and the aromatic nucleotides making up DNA and RNA) are flat — move one of the atoms out of the plane, and you decrease overlap, raise energy, etc. etc.

Except that there are 19 proteins where this isn’t the case for the 6 membered rings of phenylalanine or tyrosine.  A truly fascinating paper [ Proc. Natl. Acad. Sci. vol. 109 pp. 9414 – 9419  ’12 ] describes alpha-lytic protease (alphaLP from here on) in which phenylalanine #228 has a bent benzene ring.  Even more interestingly, this raises the energy of the protein and appears to be an integral part of the protein’s biological functioning.   It’s not an accident.

When you do Xray crystallography, 2 Angstrom resolution is usually enough to show you what’s going on (the C – C bond is 1.54 Angstroms).  However, ultrahigh resolution structures (resolutions under 1 Angstrom) have become available for some 100 proteins, allowing you to see if aromatic rings are truly flat.

Phenylalanine #228 of alphaLP is not flat at all, deviating by 6 degrees from planarity.  How much is this?  Well the benzene carbon carbon bond length is 1.4 Angstroms, so it’s 1.4 + 2 * 1.4  * sine (30) = 1.4 + 2 * 1.4  * 1/2 = 2.8 Angstroms from carbon 1 to carbon 4.  How far does 6 degrees takes carbon 4 out of the plane of carbons 1, 2 and 6? It’s 2.8 * sine 6 degrees.  Since sine 6 degrees is .10, this means that carbon 6 is only .28 Angstroms out of the plane — high resolution indeed.

Now it gets interesting, from both a chemical and biological point of view.  It turns out that, purely on an energetic basis, the unfolded form of alphaLP is 4 kiloCalories/mole lower in energy than the folded (native) form, so the native form is metastable.  However, it is kinetically stable, with a half-life for unfolding of 1.2 years, a classic example of a kinetically stable, thermodynamically unstable chemical entity.

It gets more interesting (and confusing to me) because the folding barrier is said to have a half-life of 1,800 years (4 kiloCalories/mole shouldn’t make that much difference should it?).  Does anyone out there know why the folding and unfolding barriers should be so different.  So how does the protein get into the native configuration?  By a covalently attached folding catalyst (called the pro region), which is removed when the native state is reached.  Kinetic stability seems to exact a toll on the difficulty of folding, one which selection is willing to pay.

Now it’s time to look at the environment of phenylalanine #228.  The ring is being pushed out of shape by threonine #181 below and tryptophan #199 above.  So the authors did the obvious, replacing Thr181 by glycine and then alanine and watching what happened.  The mutants unfolded faster — so the distortion in some way is raising the energy of the transition state, and thus is functionally important in the kinetic stability of the protein.   The authors are silent as to the actual structure of the transition state for unfolding, but rates are rates and their conclusions seem sound.  As they say in computer land, that’s not a bug, that’s a feature.  Why would you wan’t alphaLP to be kinetically rather than thermodynamically stable?  The authors think that kinetic stability makes alphaLP  better able to survive in harsh environments.  Perhaps

Well, how common is this?  There are some 100 protein structures now available at ultrahigh resolution.  19 of them have nonplanar aromatic side chains by 6 degrees or more (see figure 5 p. 9418).  Who’d a thunk it.  One wonders how many structures were thrown out because everyone knew that aromatic rings are planar.

What does this mean for the computational chemist?  The low energy form may not actually be the important one.  What we’ve assumed about side chains may not be true.  It makes the protein folding problem even more complicated.

They don’t discuss tryptophan planarity.  Clearly more ultrahigh resolution studies of proteins are needed.  Think of the decades spent studying proteins, and here’s something brand new.  Reading the scientific literature is like reading a Russian novel with thousands of new characters popping up and doing  the unexpected.