Diiodoacetylene: compact, strong ditopic halogen bond donor

Perkins, Catherine; Libri, Stefano; Adams, Harry; Brammer, Lee

doi:10.1039/c2ce00029f

Cited by 64 publications

(53 citation statements)

References 73 publications

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“…26 Alternatively, the intended XB donor can be connected to an sp-hybridized carbon atom which facilitates polarization and leads to an enhanced positive charge. 27,28,29 Only in very rare cases has a combination of approaches been deliberately utilized in order to create an activated XB donor. 30,31 In order to develop a new series of potent XB donors for effective co-crystal synthesis, we decided to combine the electron-withdrawing capabilities of -NO 2 moieties with the polarizing effects of an sp-carbon atom thereby providing a path to highly electrophilic halogen atoms through a 'double-activation' process, Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Crystal Engineering with Iodoethynylnitrobenzenes: A Group of Highly Effective Halogen-Bond Donors

Aakeröy

Wijethunga

Desper

et al. 2015

Crystal Growth & Design

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The benefits of employing a 'double activation' strategy for promoting effective practical cocrystal synthesis through halogen bonding was explored in a systematic supramolecular synthetic study of iodoethynylnitrobenzenes, where the positive electrostatic potential on the iodine atom was enhanced through a combination of an sp-hybridized carbon atom and one or more electronwithdrawing nitro groups. Three model compounds, 1-(iodoethynyl)-4-nitrobenzene (4N-I), 1-(iodoethynyl)-3-nitrobenzene (3N-I) and 1-(iodoethynyl)-3,5-dinitrobenzene (3,5DN-I) were synthesized and characterized, and calculated molecular electrostatic surface potential values on the halogen-bond donor site were about 20-40 kJ/mol higher than those observed for previously well-established halogen-bond donors. The ability of these molecules to drive co-crystal formation was evaluated through a total of 45 co-crystallization experiments with 15 different acceptor molecules. IR spectroscopic data for the resulting products showed that each reaction in the formation of a co-crystal driven by either C-I···N or C-I···O halogen bonds. The analogues bromo-compounds displayed a 60% success rate whereas the chloro-analogues did not yield any co-crystals, emphasizing the importance of the magnitude of the electrostatic aspects of halogen bonding for practical supramolecular synthesis. Ten new crystal structures are presented and the outcome (in terms of stoichiometry and connectivity) is largely predictable. A comparison of I···acceptor distances found in these structures with relevant data from the CSD shows that iodoethynylnitrobenzenes consistently give rise to a larger reduction of combined van der Waals radii (for C-X···acceptor) than do other well-known halogen bond donor moieties.

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Section: Introductionmentioning

confidence: 99%

Crystal Engineering with Iodoethynylnitrobenzenes: A Group of Highly Effective Halogen-Bond Donors

Aakeröy

Wijethunga

Desper

et al. 2015

Crystal Growth & Design

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“…Such information can form the basis for more reliable noncovalent synthetic strategies in the assembly of more complex supramolecular targets 6f. 11f,g…”

Section: Introductionmentioning

confidence: 99%

Supramolecular Hierarchy among Halogen‐Bond Donors

Aakeröy¹,

Baldrighi²,

Desper³

et al. 2013

Chemistry A European J

215

181

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Through a combination of structural chemistry, vibrational spectroscopy, and theory, we have systematically examined the relative structure-directing importance of a series of ditopic halogen-bond (XB) donors. The molecular electrostatic potential surfaces of six XB donors were evaluated, which allowed for a charge-based ranking. Each molecule was then co-crystallized with 21 XB acceptors and the results have made it possible to map out the supramolecular landscape describing the competition between I/Br-ethynyl donors, perfluorinated I/Br donors, and I/Br-phenyl based donors. The results offer practical guidelines for synthetic crystal engineering driven by robust and directional halogen bonds.

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“…The iodoalkynyl moiety being a robust XB donor, [7][8][9][10] we have investigated the formation of co-crystals involving 1andboth neutral and anionic electron density donor partners. Here wedescribe the adducts 4 and 5a,b obtained when 4,4'-bipyridine (2) andtetrabutylammonium iodide (3a) or chloride (3b) are used as XB acceptors.…”

Section: Co-crystal Screeningmentioning

confidence: 99%

“…7 A region of remarkably positive electrostatic potential, the so-called positive -hole, 8 is present on the outermost surface of the iodine atom and along the extension of the C-I covalent bond.This specific feature makes the iodoalkynemoiety a very good XB donorsite. 9,10 We reasoned that the presence in 1of one efficient XBdonor sitealong with the absence of strong HBdonor sites represents a unique opportunity to explore the obtainment of new cocrystals based on XB.In addition, the presence in 1of multiple electrondonor sites that may be involved in XB, e.g., the chlorine atoms, the oxygen atom, and the electrons, may favour the obtainment of different polymorphs and allow for a quite rich structural landscape for the pure API.…”

Section: Introductionmentioning

confidence: 99%

“…9,10 We reasoned that the presence in 1of one efficient XBdonor sitealong with the absence of strong HBdonor sites represents a unique opportunity to explore the obtainment of new cocrystals based on XB.In addition, the presence in 1of multiple electrondonor sites that may be involved in XB, e.g., the 2 chlorine atoms, the oxygen atom, and the electrons, may favour the obtainment of different polymorphs and allow for a quite rich structural landscape for the pure API.…”

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confidence: 99%

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Polymorphs and co-crystals of haloprogin: an antifungal agent

et al. 2014

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a Haloproginis a topical antifungal agent. Its structuredoes not contain any of the functional groups typically exploited in hydrogen bond based co-crystal design. On the other hand, its 1-iodoalkyne moiety is nicely tailored to a crystal engineering strategy based on halogen bonding. Here we describe the formation of threepolymorphs of haloprogin and of threecocrystalsthat this active pharmaceutical ingredient forms with both neutral and ionic co-crystal formers. The halogen bond plays a major role in all of the six structures and the interaction is thus confirmed to be a valuable tool which may complement the hydrogen bond when polymorph and co-crystal screeningsare pursued. IntroductionPolymorph and co-crystal screeningsareuseful strategies to find new solid forms of active pharmaceutical ingredients(APIs),in order to alter/improve their physical properties without changing their chemical identities or biological activities. 1 Most commonly APIs have hydrogen bonding donor and acceptor groups that are involved in the binding of the co-crystal former (CCF), e.g., carboxylic acids and aromatic nitrogen atoms havebeen proven particularly reliable moieties in hydrogen bonding (HB) driven formation of API-CCF adducts. 2 On the other hand, the design of pharmaceutical co-crystals involving APIs devoid of strong hydrogen bonddonor sitesisquite challenging.Halogen atoms are frequently present in drugs molecules and we considered that they can be used to drive the formation of pharmaceutical co-crystals if the halogen bonding 3 (XB) is used. Recently we demonstrated that the iodoalkyne moiety of an API can be successfully used to prepare halogen-bonded cocrystalswith improved physicochemical properties. 4 In this paper we describe a further case where the same moiety drives the formation of co-crystals with neutral and anionic partners. More important, we describe how the iodoalkyne moiety can play an active role in the formation of different polymorphs of an API.Haloprogin1(1,2,4-trichloro-5-[(3-iodoprop-2-yn-1-yl)oxy]benzene) is the API of antimycotic topical drugswith brand names of Halotex®, Mycanden®, Mycilan® and Polik® (Scheme 1). 5No structures involving 1are reported in the Cambridge Structural Database (CSD), 6 consistent with the fact that it may represent a difficult challenge if a standard approach for polymorph and co-crystal formation is pursued since it does notcontain any of the functional groupstypically required for a HB-based strategy. On the other hand, an iodine atom bound to the sphybridisedcarbon atom displays a particularly anisotropic distribution of its electron density.7 A region of remarkably positive electrostatic potential, the so-called positive -hole, 8 is present on the outermost surface of the iodine atom and along the extension of the C-I covalent bond.This specific feature makes the iodoalkynemoiety a very good XB donorsite. 9,10 We reasoned that the presence in 1of one efficient XBdonor sitealong with the absence of strong HBdonor sites represents a unique opportunity to explore t...

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Diiodoacetylene: compact, strong ditopic halogen bond donor

Cited by 64 publications

References 73 publications

Crystal Engineering with Iodoethynylnitrobenzenes: A Group of Highly Effective Halogen-Bond Donors

Crystal Engineering with Iodoethynylnitrobenzenes: A Group of Highly Effective Halogen-Bond Donors

Supramolecular Hierarchy among Halogen‐Bond Donors

Polymorphs and co-crystals of haloprogin: an antifungal agent

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