Henry Rzepa's blog

Tag: Anomer

A periodic table for anomeric centres, this time with quantified interactions.
The previous post contained an exploration of the anomeric effect as it occurs at an atom centre X for which the effect is manifest in crystal structures. Here I quantify the effect, by selecting the test molecule MeO-X-OMe, where X is of two types:
1. A two-coordinate atom across the series B-O and Al-S, and carrying the appropriate molecular charge such that X carries two lone pairs of electrons (thus the charge is 0 for O, but -3 for B).
2. A four-coordinate atom across the series B-O and Al-S, with X-H bonds replacing the lone pairs on this centre in the previous example, and again with appropriate molecule charges (e.g. +2 for SH₂).
The donor in the anomeric interaction always originates on the oxygen of the MeO group attached to X. The acceptor is always the X-O σ* empty orbital. The results (table below, ωB97XD/Def2-TZVPP calculation, NBO E(2) in kcal/mol) confirm that as X gets more electronegative, the X-O σ* empty orbital becomes a better acceptor, and so the NBO E(2) interaction energy which quantifies the anomeric interaction gets larger. Eventually (with X=OH₂) the donation of electrons into the X-O σ* empty orbital becomes so effective that the X-O bond (in this case O-O) dissociates fully and the NBO perturbation cannot be computed. Also for reference, a “normal” anomeric interaction (such as is found in e.g. sugars) is around 18 kcal/mol. Anything larger than this could be considered especially strong, and anything less than ~10 kcal/mol would be regarded as weak.

X[cite]10.14469/hpc/1221[/cite]*

BH₂ CH₂ NH₂ OH₂

12.5 17.7 18.5 dissociates

AlH₂ SiH₂ PH₂ SH₂

6.9 12.9 21.9 31.3

B C N O

8.3 11.7 12.9 14.2

Al Si P S

4.8 6.6 11.2 18.2

For the entry X=S, the E(2) term is actually larger than for the oxygen. I should note that the Me group itself is not passive in this process. The C-H bonds can also act as significant electron donors, but here I am not going to analyse this additional complexity.

This table reveals that there is nothing special about carbon as an anomeric centre, and here also the normal intimate association with the term anomeric and heterocyclohexanes such as found in sugars.

* Here I introduce a refinement to my normal process of citing the data produced for any specific calculation. Rather than including 16 individual citations for each cell in the table, I have gathered all these calculations into a collection and cite here only the DOI of that collection. When resolved, the individual members of that collection can then be inspected for the actual data.
August 8, 2016
A periodic table for anomeric centres.

In the last few posts, I have explored the anomeric effect as it occurs at an atom centre X. Here I try to summarise the atoms for which the effect is manifest in crystal structures.

The effect is defined by X bearing two substituents, one of which Z is a centre bearing a “lone pair” of electrons (or two electrons in a π-bond), and another Y in which the X-Y bond has a low-lying acceptor or σ* empty orbital into which the lone pair can be donated. This donation will only occur if the Z-lone pair and the X-Y bond vectors align antiperiplanar. Here is the summary so far.

X Blog entry

B 16601

C 14508,8898

N this one

O 16646

Si 16601

P 16601

S this one

As required of a good periodic table, it has gaps that need completing, in this case X=N and X=S. Firstly N, for which the small molecule below is known (FUHFAP).

A ωB97XD/Def2-TZVPP calculation[cite]10.14469/ch/195294[/cite] yields an electron density distribution, which can be collected into monosynaptic basins using the ELF technique. There are two oxygen lone pairs (17 and 20) that are close to antiperiplanar to the adjacent N-O bond, having E(2) interaction energies obtained using the NBO method of 15.1 and 15.8 kcal/mol, typical of the anomeric range. The basin labelled 13 on X=N1 below is also perfectly aligned antiperiplanar with the adjacent O3-C2 bond, but its E(2) interaction energy is only 7.3 kcal/mol. Thus a strong anomeric interaction on the anomeric atom itself does not seem to occur. The same effect was noted for X=O in the previous post; the explanation remains unidentified.

With the X=S gap, we have lots of opportunity with polysulfide compounds, a good example of which is the C₂-symmetric and helical S₈ dianion TEGWAF[cite]10.5517/CCYKJ88[/cite]

Each of the 8 sulfur atoms exhibits antiperiplanar orientation of an S lone pair with an adjacent S-S acceptor σ* orbital;
1:2-3=23.7 kcal/mol;
2:3-4=18.5;
3:4-8=11.7, 3:2-1=7.4;
4:8-7=11.4, 4:3-2=9.2.

This just surveys the central main group elements, and it is possible that this little mini-periodic table may yet grow.

August 6, 2016
Anomeric effects at carbon involving lone pairs originating from one or two nitrogens.

The previous post looked at anomeric effects set up on centres such as B, Si or P, and involving two oxygen groups attached to these atoms. Here I vary the attached groups to include either one or two nitrogen atoms.[cite]10.14469/hpc/936[/cite]

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The plot below shows aminols, C(NHR)(OR”). A torsion along either the C-O or C-N bond of ~60° implies that (at two coordinate oxygen or three coordinated nitrogen) there may be a lone pair with a torsion of 180°, which would set up an antiperiplanar alignment between that lone pair and the adjacent C-O or C-N bond (the anomeric effect). The clear hotspot is at angles of ~80°, which does raise the issue of why it deviates from 60°. Only a location of the lone pair centroid (using eg the ELF quantum mechanical technique) would cast light on that. There is a less distinct region for which the C-N torsion is 60° and the C-O torsion 180°, and an even less distinct region for the reverse (C-O torsion is 60° and the C-N torsion 180°). This tends to imply that a nitrogen lone pair is a better donor into a C-O bond than the reverse. Electronegativity suggests this should indeed be so, with the N lone pair less bound by the N nucleus and hence easier to release into a C-O^σ* orbital which is a better acceptor than then equivalent C-N^σ* orbital. This plot is where both heteroatoms are nitrogen (geminal diamines). There are about twice as many examples, resulting in more distinct clustering. The anomeric hotspot is now around 70° and there are equally populated clusters where only one torsion is ~70°. There is another cluster for which both torsions are 180° (no stereoelectronic alignment of lone pairs) and three small clusters where the torsions are either 180° or 0°. There is finally an intriguing cluster for which both torsions at ~120° (again no stereoelectronics).

Searches like this seem to be good at creating more questions than they answer. Clearly, the origins of the various hotspots need to be investigated, ideally using quantum mechanics to quantify the stereoelectronic interactions involved. So this sort of (ten minute) exercise is very good at raising research project investigations.

July 8, 2016
Anomeric effects at boron, silicon and phosphorus.

The anomeric effect occurs at 4-coordinate (sp³) carbon centres carrying two oxygen substituents and involves an alignment of a lone electron pair on one oxygen with the adjacent C-O σ*-bond of the other oxygen. Here I explore whether other centres can exhibit the phenomenon. I start with 4-coordinate boron, using the crystal structure search definition below (along with R < 0.1, no disorder, no errors).[cite]10.14469/hpc/696[/cite]

The result shows two prominent clusters, one with both torsion angles being 180°, and another with both being ~60°. This latter is the one that implies that there must be two lone pairs, one on each oxygen, that are anti-periplanar to the adjacent B-O bond. There are two more diffuse clusters where only one antiperiplanar alignment is seen. So yes, 4-coordinate boron can exhibit an anomeric effect!

This compares to the carbon-anomeric plot which is shown here for comparison, where the top right cluster of 180° torsions contains proportionately few hits than with boron.

The next centre is at 4-coordinate silicon. Again three significant clusters are seen; one with two antiperiplanar lone pair alignments with Si-O bonds, and two more with just one such alignment. The previous hotspot for which both measured torsions were 180° is largely absent. So here, the anomeric effect is much stronger. Notice also that whereas the torsions in the region of 60° for the carbon centre lie along a ridge coincident with the diagonal (bottom left to top right), that for the silicon centre show a ridge running orthogonal to the diagonal. An interesting point to follow up perhaps?

Since the off-diagonal clusters are relatively prominent, implying just one anomeric interaction, it is of interest to see if this results in any asymmetry in the two Si-O bond lengths. If its present, the effect is small.

Finally 4-coordinate group 15 elements. Most of the hits are in fact for P; there are none for N. This shows four clusters; the two on the diagonal show respectively two and no antiperiplanar interactions. The two off-diagonal clusters show just one such orientation. As with Si, the ridge in the 60° region run orthogonal to the diagonal.

So this little exploration shows that the anomeric effect, best known for sugars and at a carbon centre, is in fact more general to the adjacent elements.

July 1, 2016
The geometries of 5-coordinate compounds of group 14 elements.
This is a follow-up to one aspect of the previous two posts dealing with nucleophilic substitution reactions at silicon. Here I look at the geometries of 5-coordinate compounds containing as a central atom 4A = Si, Ge, Sn, Pb and of the specific formula C₃4AO₂ with a trigonal bipyramidal geometry. This search arose because of a casual comment I made in the earlier post regarding possible cooperative effects between the two axial ligands (the ones with an angle of ~180 degrees subtended at silicon). Perhaps the geometries might expand upon this comment?

The search query is shown above results in 394 hits (May 2016) and is presented with the three variables in the query plotted as below, with the O-4A-O angle indicated by colour (red ~ 180°; blue ~90° and green ~120°).
1. The cluster at distances of 4A-O of ~1.9Å represents silicon compounds, and tends to suggest that the pair of distances 4A-O are quite similar in value. The angles correspond to a di-axial arrangement around the silicon. In this scenario, one might imagine a stereoelectronic effect similar to the anomeric effect when 4A = C operates and which has the potential to strengthen both di-axial oxygens.
2. The bulk of the points come at higher 4A-O distances of > 2.1Å and consist mostly of 4A = Sn. There are two a clear-cut distributions, one for angles of ~180° and a separate one for angles of ~90° and both are qualitatively different from the Si distribution. The 180° set corresponds to a di-axial arrangement for the oxygens, whereas the 90° set suggests an axial-equatorial geometry. Both distributions have prominent tails which reveal that as one 4A-O distance shortens, the other lengthens, equivalent to asymmetric anomeric effects at O-C-O.
3. Noticeably absent are any green points; these would correspond to bond angles of ~120° and hence would correspond to di-equatorial ligands.
This quick exploration (with potential variations that I have not explored above) can be added to the collection of "ten minute explorations" I have described elsewhere.[cite]10.1021/acs.jchemed.5b00346[/cite]
May 30, 2016
The formation of tetrahedral intermediates.
In the preceding post, I discussed the reaction between mCPBA (meta-chloroperbenzoic acid) and cyclohexanone, resulting in Baeyer-Villiger oxidation via a tetrahedral intermediate (TI). Dan Singleton, in whose group the original KIE (kinetic isotope measurements) were made, has kindly pointed out on this blog that his was a mixed-phase reaction, and that mechanistic comparison with homogenous solutions may not be justified. An intriguing aspect of the (solution) mechanism would be whether the TI forms quickly and/or reversibly and what the position of any equilibrium between it and the starting ketone is. This reminded me of work we did some years ago,[cite]10.1021/jo00389a050[/cite] and here I discuss that.

It involved the addition of phenyl hydroxylamine, PhNHOH to acetyl cyanide at 215K. Because the CN group is poor at leaving, the tetrahedral intermediates do not collapse and instead accumulate in seconds to the point of becoming detectable by NMR (both N-C and O-C isomers). The position of the equilibrium clearly favours the TI rather than the starting materials. In another context, both the rate of reaction and the equilibrium can be driven towards the TI by the application of pressure.[cite]10.1039/P29870001477[/cite] Hydroxylamines are known to be super nucleophiles, enhanced by the so-called α-effect from buttressing of adjacent lone pairs on the N and O. This reminds that a peracid also should exhibit a related α-effect; it should be a better nucleophile than a normal carboxylic acid. So I decided to take the TI formed from cyclohexanone and mcPBA and look at the NBO orbitals, which should tell us about the anomeric effects present in this TI, and in particular if they might be larger than normal (which could be equated with greater stability for the TI). Here are the relevant NBO energies.[cite]10.14469/ch/191327[/cite]
1. The conventional anomeric effect in O-C-O manifests as a E(2) perturbation energy of ~16-18 kcal/mol between one oxygen lone pair and the antibonding C-O orbital. There are two combinations, and these are normally similar in energy.
2. For the system above, the O1-C2-O6 interaction is 25.6 kcal/mol, much larger than normal, but partially counterbalanced by:
3. O6-C1-O2 =13.0 kcal/mol which is a little lower than normal. This is overall an unusually strong anomeric effect for the O-C-O motif!
4. The energetic asymmetry is matched by the two computed bond lengths, 1.381Å for the larger interaction and 1.455Å for the smaller. The pseudo-α-effect has desymmetrized the anomeric effect, but nevertheless strengthened it overall.
NBO 103 for O1(Lp)

NBO 97 for O6(Lp)

NBO 123 for C2-O6 antibonding σ^*orbital

One concludes that the asymmetric anomeric effect makes the TI resemble the reactants. The transition state leading to the TI must be even earlier. In this context, I note that the (mixed phase) ¹³C effect reported for the carbonyl by Singleton and Szymanski[cite]10.1021/ja992016z[/cite] was quite a large one for carbon (1.045-1.051), a magnitude which argues against a very early transition state under these conditions. But the calculated value for a homogenous solution state model of ~1.023 is certainly more in accord with an early transition state.

Finally, a search of the CSD reveals 12 molecules containing either a O-O-C-O-O or a O-C-O-O sub unit This one[cite]10.1021/jf00032a025[/cite] shows a bis HO-C-O-O-C-OH structure at room temperature; these species need not be unstable! There are none however with Ac-O-O-C-O. And of course the potent antimalarial artemisinin contains a O-O-C-O-C-O-Ac unit, for which stereoelectronic effects may also be important.
June 12, 2015

X[cite]10.14469/hpc/1221[/cite]*
BH₂	CH₂	NH₂	OH₂
12.5	17.7	18.5	dissociates
AlH₂	SiH₂	PH₂	SH₂
6.9	12.9	21.9	31.3
B	C	N	O
8.3	11.7	12.9	14.2
Al	Si	P	S
4.8	6.6	11.2	18.2

X	Blog entry
B	16601
C	14508,8898
N	this one
O	16646
Si	16601
P	16601
S	this one

Tag: Anomer

A periodic table for anomeric centres, this time with quantified interactions.

A periodic table for anomeric centres.

Anomeric effects at carbon involving lone pairs originating from one or two nitrogens.

Anomeric effects at boron, silicon and phosphorus.

The geometries of 5-coordinate compounds of group 14 elements.

The formation of tetrahedral intermediates.