news & views alkyl chains are the solvophilic part. These alkylated fullerene molecules phase-separate at the nanoscale owing to the energetic mismatch of C60 moieties with n-alkanes to induce a solvophobic interaction, which results in supramolecular organization into nanostructures. Micelles with π-conjugated cores and alkyl shells were observed and characterized at low concentrations using an impressive variety of techniques, including small-angle X-ray and neutron scattering measurements and cryo-transmission electron microscopy. A question that looms large at this stage is whether the structural diversity of conventional amphiphiles can also be displayed by these hydrophobic systems. On studying C60 alkylated with highly branched chains, the team observed gelation in n-alkanes at higher concentrations, hinting at a fibrillar morphology. This notion was confirmed by X-ray scattering and diffraction studies, which showed the presence of fibres comprising hexagonally packed C60 columns. Photoconductivity measurements performed using microwave conductivity techniques showed values that are close to crystalline C60, suggesting that the impact of amphiphilic ordering on the functional properties is negligible, and that the addition of the non-conducting solvent has no negative effect. Remarkably, formation of lamellar mesophases was achieved without the presence of a solvent by co-assembling pristine C60 with the liquid C60-alkyl derivative. Pristine C60 interacts with the C60 part in the molecules and, owing to their mutual compatibility, results in the growth of lamellar thermotropic mesophases, demonstrating that selfassembly of such molecules can also be induced in an unprecented way by addition of solvophobic π-conjugated additives. Apart from the conceptual novelty of hydrophobic amphiphiles, if one instead
considers potential applications, organicsemiconductor-based optoelectronics could benefit from supramolecular chemistry 6. It has been shown that supramolecular ordering of π-conjugated molecules is critical for efficient optoelectronic devices, as ordering results in efficient exciton diffusion and electron transport. However, many supramolecular strategies are known to increase order only on scales of around tens of nanometres, which leads to multidomains in bulk materials. For devices to be fabricated from such materials, control over larger scales is a rudimentary prerequisite. In the field of functional organic materials this is one of the grand challenges: control over order at all length scales going from molecules to devices. In this respect, liquid crystallinity would be beneficial for achieving longrange order because manipulation on the nanometre scale can result in materials with a monolithic structure on macroscopic length scales. Amphiphilicity combined with liquid crystalline order could be a useful combination. Hollamby, Nakanishi and co-workers have not only expanded the limits of amphiphilic molecules, but have also controlled the self-assembly of C60 fullerenes, an important n-type organic semiconductor. If liquid crystalline mesophases can be formed from these selfassemblies, a rejuvenation of supramolecular electronics could be imminent. Unquestionably, the ‘hydrophobic amphiphile’ approach shows great promise for organizing π-conjugated systems, and these initial studies open the door for more detailed investigations. For example, investigating whether the principle can be generalized to other π-systems seems to be the next logical step. Although various phases have been observed for these π-conjugated–alkyl systems, a general
concentration-dependent phase behaviour — characteristic of classical amphiphiles — is still to be realized. Moreover, for molecules to realize their true potential as devices, macroscopic order is required. Considering the present impetus of this work, assembling functional materials with a monolithic structure on macroscopic length scales seems a viable route to take. Furthermore, it is interesting to consider a generalization of the addition of pristine solvophobic π-conjugated systems to π-conjugated systems equipped with alkyl tails. One could think about adding other carbon systems such as carbon nanotubes and graphene to the π-conjugated–alkyl molecules. Multicomponent systems, in which p-type π-conjugated building blocks and n-type moieties are incorporated, could be exploited through their differential solubility, thus ushering in a new dimension to optoelectronic devices such as solar cells. By providing a plethora of opportunities in a field that was thought to have been destined primarily for aqueous systems, the ‘muchness’ of amphiphilicity seems to have now been restored. ❐ Albert P. H. J. Schenning is at the Laboratory of Functional Organic Materials and Devices, and the Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands. Subi J. George is at the New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore-560064, India. e-mail: [email protected]; [email protected] References 1. Carroll, L. Alice’s Adventures in Wonderland and Through the Looking-Glass (ed. Hunt, P.) (Oxford Univ. Press, 2009). 2. Hollamby, M. J. et al. Nature Chem. 6, 690–696 (2014). 3. Sorrenti, A., Illa, O. & Ortuño, R. M. Chem. Soc. Rev. 42, 8200–8219 (2013). 4. Hardy, W. B. Nature, 112, 537–537 (1923). 5. McBain, J. W. & Salmon, C. S. J. Am. Chem. Soc. 42, 426–460 (1920). 6. Hoeben, F. J. M. et al., Chem. Rev. 105, 1491–1546 (2005).
A radical revolution in synthesis
A newly designed thiol catalyst for radical cyclization reactions is the result of a long and storied battle to control the reactivity of carbon-centred radicals.
Andrew F. Parsons
ince Gomberg first discovered a carboncentred radical (Ph3C·) in 1900, the widespread use of radicals in organic synthesis has faced a number of challenges. Although the formation and reaction of
carbon-centred radicals (of the form R3C·) has been exploited on a large scale in the chemical industry to make polymers, approaches using radicals are rare for small-molecule targets, such as medicines and agrochemicals.
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Concerns over using carbon-centred radicals in synthesis have included: a lack of clean, environmentally friendly methods for their formation; their high reactivity and potential to form a 659
news & views Reagent-controlled strategy
Complex-controlled strategy O
Reaction on the bottom face
Reaction on the top face
LA* = chiral Lewis acid
AcO AcO AcO
Me O OAc
Figure 1 | Enantioselective reaction of a carbon-centred radical. Reaction at one of the two faces of the radical can be favoured using either a complex-controlled strategy, using a chiral Lewis acid, or a reagent-controlled strategy by using a chiral hydrogen-atom donor.
number of products, in low yields; the lack of stereoselective radical reactions to produce predominantly, or exclusively, one diastereoisomer and/or enantiomer. Gradually, however, as a result of the work of devoted radical enthusiasts, the situation is changing. Pioneering work by physical organic chemists showed that different carbon-centred radicals typically react at different rates with the same substrate, providing an understanding of the steric and electronic factors that affect their reactivity. This understanding makes it possible to design efficient ways to prepare small molecules using radicals as intermediates, commonly in chain reactions. Radicals have, for example, been widely exploited in the selective formation of 5- and 6-membered rings1. The ability to selectively form a carbon-centred radical and then efficiently ‘trap’ the radical product of a cyclization reaction has led to the inclusion of radical methods within elegant approaches to structurally complex natural products2. Many of these developments are thanks to the use of a single reagent — tributyltin hydride (Bu3SnH). Bu3SnH is such a useful reagent in radical (chain) reactions, for three reasons:
(i) It contains a particularly weak Sn–H bond, which is selectively broken under mild conditions, to form the Bu3Sn· radical. (ii) The Bu3Sn· radical reacts with starting materials such as organohalides (RX) to selectively form carbon-centred radicals (R·). (iii) After reaction of the first-formed radical (R· → Rʹ·), Bu3SnH is highly effective at ‘trapping out’ the product radical (Rʹ·), by donating a hydrogen atom and reforming the Bu3Sn· radical. The toxicity associated with organotin compounds, however, combined with difficulties in purification of the product, have limited the use of Bu3SnH, particularly in the pharmaceutical industry. Consequently, radical devotees have turned their attention to developing cleaner, more environmentally friendly reagents3. The final formidable challenge — one that is key for all modern synthetic chemists — is the development of highly stereoselective reactions. Following pioneering work in the 1980s, numerous examples of diastereoselective reactions of carboncentred radicals have been reported4,5, but the development of enantioselective reactions has been slower 6. One frequently reported concern is that carbon-centred
Stereoselective cyclization, then fragmentation R*S
Addition then fragmentation R
Figure 2 | Catalytic cycle for the reaction of a chiral thiyl radical (R*S·, green) with a vinylcyclopropane (orange) and vinyl ether (purple) to form a substituted cyclopentane enantioselectively. 660
radicals are generally planar. If a chiral carbon atom is converted into an intermediate carbon-centred radical, then a racemic product is typically formed — because the intermediate carbon-centred radical is planar, and reacts with equal rates at both faces. But, this is also true for (planar) enolates, and so it is perhaps unsurprising that a number of ‘tricks of the trade’ have translated from enantioselective reactions of enolate ions to radical chemistry (Fig. 1). The goal is to ensure that the transition states for reaction at each of the two faces are of different energy. This can be done by complexing the radical with a chiral Lewis acid. On complexation, the two faces of the radical become diastereotopic, and react at different rates, thereby selectively forming one enantiomer. For example, the steric bulk of a chiral ligand on a Lewis acid can hinder the approach of a reagent to one face of the radical. To achieve high enantioselectivity using substoichiometric or catalytic amounts of the Lewis acid, however, requires that there is little or no background reactivity. An alternative to the aforementioned ‘complex controlled’ strategy, is a ‘reagent controlled’ approach (Fig. 1). Here, a chiral reagent reacts with the planar carbon-centred radical so that, once again, the transition states formed from reaction on either face of the radical will have different energies. Following on from the productive use of Bu3SnH, some ground-breaking studies focused on forming a chiral hydride by replacing the butyl groups with chiral binaphthyl groups. To avoid the problems of using organotin reagents, others have sought to use hydrides bearing weak Si–H, P–H or S–H bonds. Notably, in the 1990s, Roberts examined chiral thiol catalysts7. The weak RS–H bond in a thiol means that, like Bu3SnH, it can donate a hydrogen atom to a carbon-centred radical.
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news & views Interestingly, when a chiral thiol (R*SH) reacts with a prochiral carbon-centred radical (R1R2R3C·), it can form the reduced product (R1R2R3CH) enantioselectively. A chiral thiyl radical (R*S·) is also formed that can be converted back into the thiol, so the reaction can be controlled using only a catalytic amount of the thiol. Inspired by these studies on asymmetric C–H bond formation, Maruoka and colleagues now describe8, in Nature Chemistry, the design of a chiral thiol catalyst to probe asymmetric C–C bond formation. The strategy relies on reaction of the chiral thiyl radical with a vinylcyclopropane followed by a vinyl ether, to assemble a carbon-centred radical that undergoes cyclization (Fig. 2). Crucially, the chiral group (derived from the thiyl radical) ensures the cyclization is diastereoselective and enantioselective but then on cyclization reforms the chiral thiyl radical (which can re-enter the catalytic cycle).
Maruoka and colleagues’ use of thiol catalysts bearing variously substituted chiral binaphthyl groups provided a proof of concept, and then their molecular modelling studies aided the design of a novel chiral thiol. Impressively, use of only 3 mol% of this thiol gave cyclopentanes, in good yields, with high levels of diastereoselectivity (>97:3) and enantioselectivity (up to 93% e.e.). It could be argued that the synthesis of the chiral thiol catalyst is long-winded and time-consuming, and that thiols are not always the most popular reagents because of their pungent odours. But it could equally be said that the mild reaction conditions (UV irradiation, using a peroxide, in toluene at temperatures between 0 °C and room temperature) and the formation of various cyclopentanes is impressive, as is the absence of any toxic and/ or expensive metal-based reagents. Indeed this research adds to the growing swath of activity in organocatalysis9, which has a variety of environmental benefits.
Hopefully, this work will inspire more researchers to challenge dogma and foray into the world of enantioselective radical chemistry — there are some enticing rewards for those brave enough to join the revolution. ❐ Andrew Parsons is in the Department of Chemistry at the University of York, Heslington, York YO10 5DD, UK. e-mail: [email protected] References 1. Majumdar, K. C., Basu, P. K. & Mukhopadhyay, P. P. Tetrahedron 60, 6239–6278 (2004). 2. Parsons, P. J., Penkett, C. S. & Shell, A. S. Chem. Rev. 96, 195–206 (1996). 3. Walton, J. C. & Studer, A. Acc. Chem. Res. 38, 794–802 (2005). 4. Smadja, W. Synlett. 1–26 (1994). 5. Bar, G. & Parsons, A. F. Chem. Soc. Rev. 32, 251–263 (2003). 6. Zimmerman, J. & Sibi, M. P. Top. Curr. Chem. 263, 107–162 (2006). 7. Haque, M. B. & Roberts, B. P. Tetrahedron Lett. 37, 9123−9126 (1996). 8. Hashimoto, T., Kawamata, Y. & Maruoka, K. Nature Chem. 6, 702–705 (2014). 9. List, B. Chem. Rev. 107, 5413–5415 (2007).
The road less travelled to amination Intramolecular aliphatic C–H amination reactions are greatly sought-after for the synthesis of N-containing heterocycles, but current methods require the use of highly activated nitrogen sources. Now, aziridination and lactamization have been achieved using fully aliphatic, unactivated, secondary amines.
Olga V. Zatolochnaya and Vladimir Gevorgyan
t is difficult to overstate the importance of nitrogen-containing heterocycles, due to their prevalence among both biologically active natural products and synthetic pharmaceuticals. As such, development of methods for the formation of carbon– nitrogen bonds has become a central topic in modern synthetic organic chemistry (Fig. 1a). Introducing nitrogen functionalities directly into unactivated aliphatic substrates through catalytic functionalization of C–H bonds represents a powerful approach towards achieving this goal1. So far, several intramolecular strategies have been established that all employ highly activated nitrogen sources — carbamates2, sulfamates3,4, amides5–8 or azides9,10 — to achieve C–H functionalization and efficient nitrogen-atom transfer (Fig. 1b). For example, methods developed by Du Bois and co-workers2,3 rely on the formation of rhodium nitrenoids from carbamate and sulfamate precursors under oxidative conditions. In alternative approaches by Daugulis5, Chen6 and co-workers picolylamides were employed, which were
shown to be a capable nitrogen source, as well as having their well-known potent directing properties. Although all are powerful techniques for the introduction of nitrogen-based functionalities into aliphatic molecules, these methods are unable to provide a route towards tertiary amines, which are crucial structural motifs in numerous alkaloids. Therefore, the development of methods for direct N–H/C–H coupling of secondary amines and unactivated alkanes is highly desirable. Writing in Nature, Gaunt and co-workers now show 11 that this process is not impossible. Using a palladium-catalysed C–H activation reaction, fully aliphatic unactivated amines were converted into aziridines. Additionally, a secondary amine moiety was engaged as an efficient directing group for C–H functionalization of alkanes (Fig. 1c). Gaunt and co-workers discovered that sterically demanding cyclic secondary amines underwent a facile methyl group activation in the presence of palladium acetate, forming strained four-membered ring palladacycle 1. The team rationalized that cyclopalladation of
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secondary amines occurs efficiently due to a combination of the strong Pd–N affinity and the steric demand created by α-substitution of the substrate. In other words, instead of forming an inert bisamine complex, palladium strongly binds only a single amine molecule; this opens a coordination site and facilitates a C–H activation event. Remarkably, formation of a fourmembered-ring adduct is preferred over the kinetically favourable five-membered-ring analogue, as shown in an intramolecular competition experiment. The possibility of γ-C–H activation was also established in the absence of primary β-C–H bonds. The latter results further emphasize the efficacy of aliphatic amines in serving as general directing groups for palladium-catalysed C–H functionalization. Furthermore, under oxidative conditions, strained palladacycle 1 was smoothly converted into aziridine 2 upon reductive elimination of palladium, with the accompanying formation of a C–N bond. Combining these findings, an efficient catalytic transformation of aliphatic 661
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