EurJOC Minireview European Journal of Organic Chemistry doi.org/10.1002/ejoc.202000512 Strained Carbocycles Highly Strained Unsaturated Carbocycles Raffaella Bucci,[a][‡] Nikki L. Sloan,[a][‡] Lydia Topping,[a] and Matteo Zanda*[a,b] Abstract: Highly strained unsaturated carbocyclic rings are (SPAAC) reactions. This mini-review covers two main classes of high-energy compounds which are attracting increasing inter- compounds: 3 to 10 membered-ring cycloalkynes and trans- est – not just for their peculiar structural and reactivity features cycloalkenes, including some examples of cyclic enynes, dienes – but also as modern chemical tools for bioorthogonal and in and bridgehead alkenes. Their molecular properties, synthesis vivo chemistry, especially via inverse-electron demand Diels– and reactivity are presented and discussed, with an emphasis Alder (iEDDA) and strain-promoted azide-alkyne cycloaddition on their functionalization and reactivity. 1. Introduction highly distorted compounds have stimulated the curiosity of generations of chemists, representing the archetype of chemi- Strained hydrocarbons have traditionally represented a play- cal oddities, magically ephemeral, lasting less than a heartbeat. ground for basic researchers interested in testing the limits of However, the coming of age of bioorthogonal chemistry and creativity, imagination and synthetic skills. Fascinating and the need for reactions and reagents compatible with living sys- tems, devoid of cross-reactivity with the complex in vivo bio- [a] Dr R. Bucci, Dr N. L. Sloan, L. Topping, and Prof Dr M. Zanda Loughborough University, chemical machinery, has sparked an unprecedented mass inter- Centre for Sensing and Imaging Science, School of Science, Sir David est in this once elitist area of research. Highly strained unsatu- Davies Building, Chemistry Department, LE113TU Loughborough, rated molecules able to react via “click-chemistry”-type proc- United Kingdom esses – such as inverse-electron demand Diels–Alder (iEDDA) E-mail: [email protected] https://www.lboro.ac.uk/departments/chemistry/staff/academic-research/ and strain-promoted azide-alkyne cycloaddition (SPAAC) reac- matteo-zanda/ tions – have become extremely popular and vitally important [b] Prof Dr M. Zanda tools in biological chemistry and molecular imaging. This mini- C.N.R.-SCITEC review covers two main classes of compounds, namely cyclo- Via Mancinelli 7, 20131 Milano, Italy alkynes and trans-cycloalkenes having 3 to 10 membered-rings. [‡] Raffaella Bucci and Nikki L. Sloan contributed equally. ORCID(s) from the author(s) for this article is/are available on the WWW Some examples of cyclic diynes, enynes, dienes and bridgehead under https://doi.org/10.1002/ejoc.202000512. alkenes are also included. The aim of this article is not to review Matteo Zanda was born in Alzano Lombardo (Bergamo, Italy). After the Laurea Degree in Chemistry at the University of Milan, he moved to Politecnico di Milano where he obtained a PhD in Industrial Chemistry in 1998. He then spent one year as a postdoctoral fellow at ULP Strasbourg (France). After 3 years as a junior researcher at Politecnico, in 2001 was appointed Senior Researcher of the National Research Council. He was awarded the Ciamician Medal in 2002. In 2009 he moved to the University of Aberdeen (UK), as a Professor of Medical Technologies. In 2019 he moved to Loughborough University (UK) as Director of the Centre for Sensing and Imaging Science and Professor of Biomolecular Imaging. Zanda group′s research integrates bioorganic/ medicinal/organofluorine chemistry with translational biomedical research and molecular imaging technolo- gies, particularly Positron Emission Tomography (PET) with applications in brain, cardiovascular and oncology imaging. He is author of 200 articles, including 8 patent applications, and editor-in-chief of Thieme Chemistry′s SYNFORM. Raffaella Bucci (first from right) was born near Taranto (Italy). She graduated in Chemistry at the University of Milan in 2014. She obtained her Ph.D. in Pharmaceutical Science in 2018, under the supervision of Prof. Maria Luisa Gelmi. During her Ph.D., she completed an internship at ETH Zurich, joining the group of Prof. Helma Wennemers. For the successive two years she worked as Post-Doc on a project financed by Regione Lombardia in Prof. Gelmi's laboratories, developing new methodologies for the chemical functionalization of cellulose polymers with bioactive molecules. Currently she is a Visiting Post-doc in Prof. Zanda's research group working on the synthesis of cyclic peptidomimetics through cycloaddition reactions. Nikki L. Sloan (second from right) was born in Perth, Scotland. She graduated with a 1st class MSci degree in Chemistry from the University of Strathclyde (UK) in 2011, including an industrial placement at AstraZeneca. She obtained her PhD in 2018 from the University of Glasgow (UK), under the supervision of Dr. Andrew Sutherland, on the development and radioiodination of SPECT imaging agents. Her current research interests focus on the development of new molecular probes for biomedical imaging. Lydia Topping (second from left) received her BSc degree in Medicinal Chemistry from The University of Salford (UK) in 2019. During which she completed an Internship in the therapeutic discovery labs at Cancer Research UK developing small molecule analogues. She is currently a PhD student in Prof. Zanda's research group with her research focus on developing novel strategies of peptide cyclisation. Eur. J. Org. Chem. 2020, 5278–5291 5278 © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim EurJOC Minireview European Journal of Organic Chemistry doi.org/10.1002/ejoc.202000512 the exponentially growing area of bioorthogonal and bio-con- pulsed flash pyrolysis of 4 (Scheme 2). Consequent photolysis of jugation chemistry, for which a number of excellent specialized 5 or 6 led to 1c, which was characterized by IR and theoretically reviews are available,[1–3] but to present and discuss molecular studied by ab initio calculations.[9,10] properties, synthesis and reactivity – unavoidably including some examples of bioorthogonal chemistry – of highly strained unsaturated carbocyclic rings. Because of space limits, strained cumulene rings, such as cyclic allenes, have not been included. 2. Highly-Strained Cycloalkynes CC triple bonds possess a linear structure. Many alkynes fulfil this property, in line with their sp hybridisation, but the crystal packing of substituted alkynes often shows some deviations from the linear geometrics.[4] The most common way to distort a triple bond is to incorporate the alkyne functionality in a cy- Scheme 2. Silacyclopropyne 1c and related transformations. clic framework, with the stability of these molecules under stan- dard laboratory conditions depending on the size of the ring. A number of complex theoretical methods have been used In 1983,[5] A. Krebs used the term “angle-strained cycloalkynes” so far to study cyclobutyne, a molecule that has been at the [12] to refer to distorted cycloalkynes. More precisely, all cyclo- centre of much speculation. Ab initio calculations by Schae- [13] alkynes having a CC–R angle deformation > 10° should be fer et al. suggested that singlet and triplet cyclobutyne corre- considered “angle-strained cycloalkynes”.[5] According to this spond to energy minima. The highly reactive 7 could thus give definition and based on computational evidence, all cycloalk- two isomerization processes: thermal isomerization to butatri- ynes, from non-isolable cyclopropyne and cyclobutyne to the ene 8 or ring contraction to compound 9 (Scheme 3). highly stable cyclononyne, fall into the “angle-strained” cate- gory. Strained cycloalkynes, which were considered chemical oddi- ties at best until recently, are nowadays getting a great deal of attention because they are emerging as valuable intermediates Scheme 3. Cyclobutyne and related structures. in organic synthesis for the preparation of interesting ligands, agrochemicals, pharmaceuticals, natural products and materials, Since calculations suggested no interconversion energy bar- besides being key reagents for bioorthogonal chemistry.[6] rier between 7 and 9, the ring contraction would be immediate, making it impossible to characterize compound 7, not even with IR spectroscopy. These calculations also suggested that bi- 2.1. Cyclopropyne and Cyclobutyne cyclo[3.2.0]-hept-6-yne 10 could form as a fleeting intermediate Only theoretical investigations are present in literature regard- in the reaction of 6-halobicyclo[3.2.0]-hept-6-ene with a strong [7] ing cyclopropyne and cyclobutyne. The smallest cycloprop- base.[14] To experimentally test these calculations, halides 11 yne with tetragonal geometry, 1a (Scheme 1) is proposed to be (Scheme 4) were treated with LDA in the presence of lithium a transition state in the automerization of propadienylidene 2, thiophenolate affording thioethers 13 and 14 as products, while the planar 1b is an intermediate in the rearrangement of which may indeed be formed from the intermediate 10. Carb- 2 to cyclopropenylidene 3. The structure of cyclopropyne does ene 12 is proposed to partly form as an additional intermediate not correspond to a minimum of potential energy surface, during the process. therefore it does not represent an isolable intermediate.[8] Both 1b and 3 have also been identified in the interstellar space,[9,10] where cyclopropenylidene was reported to be the most abun- dant of all hydrocarbons. Scheme 4. Bicyclo[3.2.0]-hept-6-yne 10 and related