Nonconjugated Hydrocarbons As Rigid‐Linear Motifs: Isosteres For
Total Page：16
File Type：pdf, Size：1020Kb
DOI:10.1002/chem.201804225 Review & Materials Science NonconjugatedHydrocarbons as Rigid-Linear Motifs:Isosteresfor Material Sciences and Bioorganic and Medicinal Chemistry GemmaM.Locke,Stefan S. R. Bernhard, and Mathias O. Senge*[a] DedicatedtoProfessor Philip E. Eaton Chem. Eur.J.2019, 25,4590 –4647 4590 2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Review Abstract: Nonconjugated hydrocarbons, likebicyclo[1.1.1]- manner. In this Review article, recent developments and pentane, bicyclo[2.2.2]octane, triptycene, andcubane are a usagesofthese special, rectilinear systems are discussed. unique class of rigid linkers. Due to their similarity in size Furthermore, we focusoncovalently linked, nonconjugated and shape they are useful mimics of classic benzene moie- linear arrangements and discuss the physical and chemical ties in drugs, so-calledbioisosteres.Moreover,they also fulfill properties and differences of individual linkers, as well as an important role in material sciences as linear linkers, in their applicationinmaterial and medicinalsciences. order to arrangevarious functionalities in adefined spatial 1. Introduction cyclo[2.2.2]octane (BCO) and triptycene (Figure 1). In particular, the use of triptycene as amolecular rotor has received much Arranging functionalities in alinear fashion enablesthe altera- interest, propelled by the Nobel prize in chemistry for molecu- tion of the distance between functionalities withoutaffecting lar machines awarded in 2016.[4] the overall geometry of the molecule, and this is of high im- This Reviewaims at identifyingthe origins of rigid-linear-ali- portanceinmedical and materialsciences. This can be achiev- phatichydrocarbons and their use in functional materials, ed with nonconjugated rigid hydrocarbons (NRHs) which share while tying together the chemistry,differences and commonal- three main features for their usage in biological and material ities between thesegroups and outlining the missing compo- sciences:1)they are rigid,that is, all conformational changes nents of those dormantgroups. While there are many aspects are frozen;2)they are linear,where the arrangementofthe dif- that govern the structuralcompositionand behavior of acom- ferent functionalitieshappens in adefined spatial manner,in pound, such as quantum mechanics (e.g.,London dispersion), this case a1808 fashion;3)they are nonconjugated, as the this review will focus solelyonthe physicalbond connections formal sp3-hybridized carbon center interrupts electronic com- within the four selected NRHlinkers, taking astructural engi- munication (even though this is only partially true, as will be neering viewpoint. discussed in detail vide infra). Over the years,linear linking has been aclassic field of para- substituted benzenes and alkynes, due to the plethora of well- 2. General Aspects established cross-couplingreactions.[1] Recently however,cer- 2.1. Bicyclo[1.1.1]pentane (BCP) tain other hydrocarbons, such as cubane or bicyclo[1.1.1]pen- tane (BCP) have begun to draw attention due to their remark- Bicyclo[1.1.1]pentane (BCP) is the smallest memberofbicyclic able properties.[2,3] Besides these highly strained, rather unusu- bridged alkanes. It was first synthesized by Wiberg et al. in al hydrocarbons more common moieties are in use, such as bi- 1964 (Scheme 1).[5,6] The synthesis was achieved by an anti- Markovnikov addition of hydrogen bromide to methylenecy- clobutane 1,followed by hydrolysis of the methylester 2 and decarboxylative bromination in the presence of mercury(II)ox- ide. The final ring-closure was achievedbyaWurtz reaction of the dibromide 3 in dioxane to form BCP 4. Figure 1. Nonconjugated rigid hydrocarbons (NRHs). [a] G. M. Locke, Dr.S.S.R.Bernhard, Prof. Dr.M.O.Senge Scheme1.Synthesis of BCP according to Wibergetal.[5] SchoolofChemistry,SFI Tetrapyrrole Laboratory Trinity Biomedical Sciences Institute, Trinity College Dublin The University of Dublin, 152–160 Pearse Street, Dublin 2(Ireland) E-mail:[email protected] Different approaches for the synthesis of substituted and un- The ORCID identification number(s) for the author(s) of this articlecan be substituted BCPs are known in the literature.[7] The methods in- found under:https://doi.org/10.1002/chem.201804225. volve cyclizations, ring-expansions, and ring-contractions. 2019 The Authors. Published by Wiley-VCH Verlag GmbH&Co. KGaA. Today,most chemistryofthe BCP scaffold arises from the This is an open access article under the terms of Creative Commons Attri- bridged [1.1.1]propellane intermediate 6 by utilizingstrain bution NonCommercialLicense, whichpermitsuse, distributionand repro- duction in any medium, provided the original work is properlycited and is relief as the main driving force. Usually the generation of the not used for commercial purposes. reactive [1.1.1]propellane intermediate is carriedout according Chem. Eur.J.2019, 25,4590 –4647 www.chemeurj.org 4591 2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Review at the bond criticalpoint,[16] as apositive Laplacian was evi- dent.[17] Apositive Laplacian usually is interpreted as atypical signature of charge shift bond, abond in which the covalent– ionic resonance energy is the main factor.[18] 1 Scheme2.Preparation of [1.1.1]propellane 6. In addition, systematic theoretical studies of the J(13C–13C) nu- clear spin–spin coupling of the bridgehead–bridgehead carbon atoms reflected strong through-cageelectronic interactions, to an optimized and improved procedure developed by Szei- but with higher p-character of the central bond.[19] The invert- mies and co-workers that employs the tetrahalide 5 as the ed carbon geometry of the bridgehead–bridgehead bond, no startingmaterial (Scheme2).[8] The term propellane was first matter of the actual bond character itself–which most likely coined by Ginsburg et al. in 1966, to trivialize the lengthy will stay unrevealed–still tests current theoretical calculations names tricyclic systems require.[9] of energy and bond lengths (Table 1).[20] Further information The molecular structure of the parent BCP hydrocarbon about BCP and related propellanes can be found in other very shows some notablepeculiarities. Electron diffraction in the comprehensive reviews.[3,7, 22] vapor phase confirmed the symmetric shape(D3h)and shows one of the shortest nonbonded carbon–carbon interactions (in- terbridgehead distance of 1.845[10]/1.874 [11]). This 1,3-non- bondedrepulsionofthe bridgehead carbon atom leads to a destabilization of the BCP cage in the ground state. Moreover, it even is consideredtobeone major aspect of the overall ring Gemma Lockeobtained herBSc in Medicinal strain.[12] The inverted tetrahedral geometry of BCP is repre- ChemistryatTrinity College Dublin (TCD)in 1 [13] 2014. During this time, she did athree-month sented by the high strain energy of 68 kcalmolÀ (Table 1). internship in the University of North Carolina at Chapel Hill (UNC), working on N-centered radicalsunder the supervision of Prof. Dr.Erik Table 1. Physicalproperties of bicyclo[1.1.1]pentane. Alexanian. She is currently aPhD student underthe mentorship of Prof. Dr.Mathias O. Molecular formula C5H8 Sengecarrying out research on electron-trans- fer mimics with both cubane and triptycene boiling point[C][7] 36 8 porphyrin complexes. appearance colorlessclear liquid decomposition [8C][21] >280 1 [13] heatofformation [kcal molÀ ] 51 1 [13] strain energy [kcalmolÀ ] 68 [10] [11] C1 C2 bondlength []1.545 /1.557 Dr.Stefan Berhard studied chemistry at the À C Hbondlength []1.100[10]/1.109[11] Johannes Gutenberg-University Mainz, Germa- À bridgehead distance []1.845[10]/1.874[11] ny.Hecompleted his doctoral studies on the synthesis of opticallyactive crinine-type alka- loid precursors under the supervisionofProf. Udo Nubbemeyer in 2015. In the same year Decreasing the electron density of the relevant orbitals, for he joined the group of Prof. Dr.Mathias O. Sengeatthe Trinity CollegeDublin as apost- example, by the introduction of electron-withdrawing substitu- doctoral researcher.His current research is fo- ents at the bridgehead, leads to areductionofthe 1,3-non- cusedoncross-coupling chemistry with highly bondingrepulsion and ashorter distance between the bridge- strained alkanes and the functionalization of head carbon atoms.[14] Interestingly,this repulsion is furtherre- porphyrins. lieved by the introduction of an internal carbon–carbon bond, an unexpected stability of [1.1.1]propellane. Due to the high s- Mathias O. Senge, Dipl.-Chem.,MA, Dr rer. character,the intercaged carbon–carbon bonds are very short nat.,FTCD, studied chemistry and biochem- [15] (according to Bent‘s rule). Therefore, the true character of istry in Freiburg, Amherst, Marburg, and Lin- the centralinverted bridgehead–bridgeheadbond still remains coln. After aPhD from the Philipps Universität enigmatic (Scheme 3). Arefinedelectron density analysis of Marburg (1989)and postdoctoral studieswith K. M. SmithatUCDavis he received his habili- [1.1.1]propellane by intense synchrotron primary radiation tation in Organic Chemistryin1996 from the measurements revealed significant electron density,which is Freie UniversitätBerlin. From 1996 on he was characteristic of acovalent bond, but no chargeaccumulation aHeisenberg fellow at FU Berlin and UC Davisand held visiting professorships in Greifswaldand Potsdam. In 2002 he was ap- pointed Professor of Organic Chemistryatthe UniversitätPotsdam and since 2005 holds the ChairofOrganic ChemistryatTrinity College Dublin. He was the recipient