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The comparison of a purely hexagonal nanographene with Itami and Scott’s distorted specimen offers some clues about the influence of defects (Fig. 1b) on graphene’s electronic structure. Minor changes in connectivity of small-molecule aromatic molecules can drastically alter their electronic properties. Consider, for example, naphthalene, a C10H8 isomer where two benzenoid hexagons share an edge, and azulene, a C10H8 isomer where a heptagon and a pentagon share an edge. Naphthalene is colourless, whereas azulene — as its name suggests — is deep blue. Shifting one bond by one position completely alters the electronic properties. Should we expect analogous perturbations to the structure of graphene to have such a profound influence on its electronic characteristics?

Scott, Itami and co-workers’ distorted nanographene hints at the answer to this question. Ultraviolet–visible absorbance spectroscopy reveals that the lowest-energy optical transition of the warped compounds occur at slightly higher energy than those of

the analogous fully hexagonal flat systems, but the difference (0.16 eV) is small. The change in electrochemical behaviour is, however, more significant. The distorted nanographenes show reversible reduction and oxidation behaviour via stable, charged intermediates, and suggests that pentagonal and heptagonal defects in graphene can trap charges. In all fairness, the insolubility of the fully hexagonal planar systems precludes these electrochemical measurements from being made, so a direct comparison between the flat and distorted nanographenes is impossible. Nonetheless, it is likely that heptagonal or pentagonal defects in graphene will trap charges.

For the first time we now have a reasonable model for defects in a graphitic lattice that gives us some insight into how they will affect the properties of graphene. The challenge remains to prepare the specific defects that have been observed in graphene, for example the Stone–Wales defect that gives rise to systems with two 7- and two 5-membered rings that are directly adjacent

to one another. And, looking forward, this synthesis of a distorted nanographene opens new vistas in the design and synthesis of carbon-rich materials. Unusual carbon allotropes like the pentaheptatite and Haeckelite lattices3, where pentagons, heptagons and optionally hexagons, tile the plane, and the Schwarzite lattices4, where hexagons and larger polygons form three-dimensional graphitic foams, now lie on the synthetic chemist’s horizon. ❐

Benjamin T. King is in the Department of Chemistry, University of Nevada, Reno, Nevada 89557, USA. e-mail: king@chem.unr.edu

References1. Banhart, F., Kotakoski, J. & Krasheninnikov, A. C. ACS Nano

5, 26–41 (2011).2. Kawasumi, K., Zhang, Q., Segawa, Y., Scott, L. T. & Itami, K.

Nature Chem. 5, 739–744 (2013).3. Crespi, V. H., Benedict, L. X., Cohen, M. L. & Louie, S. G. Phys.

Rev. B 53, R13303–R13305 (1996).4. Mackay, A. L. & Terrones, H. Nature 352, 762 (1991).5. Zan, R., Ramasse, Q. M., Bangert, U. & Novoselov, K. S. Nano

Lett. 12, 3936–3940 (2012).

Fast, selective and high yielding: synthetic chemists strive for such ideal reactions. Although controlling reactions that can

form multiple products is at the heart of synthetic chemistry, it remains challenging to control some of them, particularly those involving complex molecules1. Selectivity for the formation of a single product requires that the reaction producing it is significantly faster than all other competing processes. A catalyst can often help by accelerating the desired reaction and also help prevent undesired ones — by, for example, blocking the approach of reactants along trajectories that lead to undesired products.

Selectivity for the formation of a single enantiomer is frequently achieved by asymmetric catalysis. A potentially more difficult problem occurs when multiple similar sites within a substrate can react, and selectivity among them becomes crucial. Controlling which site will react can be extremely challenging, especially for biologically important molecules such as carbohydrates, DNA, peptides and natural

products. In fact, this is so challenging that site selectivity often dictates the synthetic strategy used to prepare the desired product. Managing site selectivity frequently leads to longer (and typically less efficient) synthetic sequences because of, for example, the need to employ protecting groups. Writing in Nature Chemistry, Kian Tan and co-workers describe2 how they address this problem by using catalysts that selectively and reversibly form a covalent bond to a substrate.

Enzymes are remarkable catalysts and often serve as the benchmark for both catalytic activity and selectivity. These biomolecules often achieve perfect site selectivity during the biosynthesis of natural products. Recently, several simpler synthetic catalysts behaving as enzyme mimics have been developed to achieve site selectivity1 — like enzymes, they rely on the formation of several weak interactions (for example, hydrogen bonding and hydrophobic interactions) to create a binding pocket such that reactants can only approach from one trajectory. In contrast, the catalysts developed

by Tan and co-workers rely on the concept of temporary intramolecularity — the catalyst forms a strong covalent bond to the substrate and thus favours reaction at a specific proximal site (Fig. 1). This proximity effect results in a dramatic acceleration (reactions are up to 108 times faster than intermolecular reactions)3–5 and the geometric constraints dictated by the formation of a covalent bond help to achieve site selectivity. In contrast to enzymes, however, the catalyst is much smaller and can be used for a wide variety of substrates and transformations.

The efficiency of these catalysts was put to the test using a variety of polyol natural products as substrates. Prior studies have shown that these catalysts can effectively control asymmetric reactions of simple cyclic6 and acyclic7 substrates possessing a cis-1,2-diol motif. This polyol subunit is particularly relevant to biological molecules — being found in carbohydrates, RNA and in many bioactive natural products. Tan and co-workers were thus keen to test their catalysts in a more challenging

SITE-SELECTIVE REACTIONS

Exploiting intramolecularitySelective reaction of one alcohol among many in complex molecules can be achieved by the use of a catalyst that forms a single covalent bond to a nearby functional group.

André M. Beauchemin

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environment, and have shown that they can be used to achieve site-selective transformations of polyols — even showing that selective reactions of 1,2,3-triols are possible. They first demonstrated selective functionalization of several monosaccharides — installing a variety of useful substituents (acetyl, mesyl and silyl) and showing that their catalysts can override the inherent reactivity of the substrates. For example, the least reactive axial sites in mannose, rhamnose and arabinose derivatives were all selectively functionalized using an appropriate catalyst. Next, Tan and co-workers studied the reactions of a doubly protected RNA derivative and two therapeutically useful complex natural products (mupirocin and digoxin). The functionalization of digoxin is especially impressive because this molecule contains six alcohol groups, and therefore six possible reactive sites. However, the catalysts’ mode of recognition — targeting 1,2-diols — results in selective functionalization of the terminal saccharide unit of the molecule (Fig. 1c). The three-dimensional structural requirements (stereochemistry) of the catalyst then allows control of the reaction’s outcome, with the use of catalyst (–)-1 forming α-acetyldigoxin whereas its pseudo-enantiomer (+)-2 affords β-acetyldigoxin.

The diversity of compounds that have been derivatized and a demonstration that the reactions are reliable on a gram

scale already suggests that this work can be used to engineer shorter approaches to polyol derivatives. Importantly, a critical mass of results is provided, which allows prediction of the outcome (and likelihood of success) in many other cis-1,2-diol systems. Furthermore, other catalytic acyl, sulfonyl and phosphoryl transfer reactions should be possible based on these results.

Aside from the obvious synthetic utility the work by Tan and co-workers raises many important questions about catalytic approaches using temporary intramolecularity. Such reactions are complex, requiring both preassociation (of substrate and catalyst) and then dissociation steps for catalyst turnover to occur. How fast is this preassociation step and how reversible is it? What is the impact of the catalyst structure on the possible rate accelerations, and on catalyst activity as measured by turnover numbers and frequencies? What are the sources of catalyst inhibition? And what types of substrate, catalytic transformation and reaction type can benefit from catalysis using temporary intramolecularity? Despite many unanswered questions, recent developments on catalysis using temporary intramolecularity already suggest its broad applicability providing that an ‘anchor’ group is available to interact with a catalyst3 or catalytic directing group8. Nevertheless, this work represents a milestone in the field, because it demonstrates the applicability of

this approach to a variety of substrates and high selectivity for transformations that would otherwise be very difficult to achieve.

Overall, by achieving site-selective functionalization of various polyol substrates, Tan and co-workers have shown that a catalyst preassociation subunit can operate efficiently via the formation of a single covalent bond rather than by relying on an enzymatic-type preassociation event involving several weaker interactions. These results show that catalyst design can be preassociation-centric9, and that catalysts operating by temporary intramolecularity can ultimately transform the repertoire of tools available for the preparation of biologically important molecules. ❐

André Beauchemin is in the Department of Chemistry at the University of Ottawa, Ottawa, Ontario K1N 6N5, Canada. e-mail: abeauche@uottawa.ca

References1. Mahatthananchai, J., Dumas, A. M. & Bode, J. W. Angew. Chem.

Int. Ed. 51, 10954–10990 (2012).2. Sun, X., Lee, H., Lee, S. & Tan, K. L. Nature Chem.

5, 790–795 (2013).3. Tan, K. L. ACS Catal. 1, 877–886 (2011).4. Pascal, R. Eur. J. Org. Chem. 1813–1824 (2003).5. Guimond, N., MacDonald, M. J., Lemieux, V. &

Beauchemin, A. M. J. Am. Chem. Soc. 134, 16571–16577 (2012).6. Sun, X., Worthy, A. D. & Tan, K. L. Angew. Chem. Int. Ed.

50, 8167–8171 (2011).7. Worthy, A. D., Sun, X. & Tan, K. L. J. Am. Chem. Soc.

134, 7321–7324 (2012).8. Rousseau, G. & Breit, B. Angew. Chem. Int. Ed.

50, 2450–2494 (2011).9. Tan, K. L., Sun, X. & Worthy, A. D. Synlett 23, 312–325 (2012).

a

b

c

Figure 1 | Catalytic approaches to site-selective functionalization of complex molecules. a, Enzymes and enzyme mimics: substrate (S) recognition is specific and performed using multiple weak interactions. b, Small-molecule ‘scaffolding’ catalyst: site-selective activation (A) is performed by temporary formation of a single covalent bond and by proximity (tether geometry). c, Rationale for selectivity observed in the selective functionalization of digoxin at position 2 using catalyst (–)-1.

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