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Stereoelectronic effects on dienophile separation influence the Diels-Alder synthesis of molecular clefts Martin J. Stoermer,[a] Wasantha A. Wickramasinghe,[a] Karl A. Byriel,[a] David C. R. Hockless,[b] Brian W. Skelton,[b] Alexandre N. Sobolev,[b] Allan H. White,#[b] Jeffrey Y. W. Mak,[a] David P. Fairlie[a]* Abstract: The formal cycloaddition adduct of 1,4-benzoquinone with two equivalents of cyclopentadiene is a scaffold with two non-conjugated alkenes. Both alkenes undergo endo [4+2] cycloaddition with a diene to form a rigid U-shaped molecular cleft. Here we show experimental, computational and structural evidence that pi interactions between the alkenes affect structural rigidity, Diels-Alder reactivity, cleft formation and host-guest capture.

Proteins are proficient at trapping small molecules within their clefts, and there have been many attempts to create synthetic molecules that can mimic the host-guest chemistry of proteins.[1] We have been interested[2] in using compound 1, the formal adduct of 1,4-benzoquinone with two equivalents of cyclopentadiene,[3] as a scaffold for creating molecular clefts. The two norbornene components of 1 are syn to each other on the cyclohexanedione core, with the alkenes in close proximity on the exo face of the tricyclic system. Diels-Alder reactions of each dienophilic alkene in 1 with a diene could produce two parallel faces roughly perpendicular to the scaffold to give a U-shaped molecular cleft. The electronic behavior (LUMO and HOMO) and reactivity of bis-alkenes such as norbornadiene,[4] bicyclo-[2.2.2]octa-2,5-diene,[5] and tetrahydroanthracene[6] in Diels-Alder reactions are known to be strongly influenced by the spatial proximity of their non-conjugated alkenes.[6,7] The alkenes in 1 are thought to closely approach each other, since they are able to undergo a photo-induced [2+2] cycloaddition to form a caged adduct.[3] These findings support p-p interaction between the non-conjugated alkenes in these molecules. Here, we investigate how p-p interactions in 1 (Scheme 1) might be affected by substituents on its cyclohexanedione core, and what impact these interactions have on the Diels-Alder reactions of 1 to form molecular clefts.

Scheme 1. Diketone 1 is difficult to reduce to diols 2 or 3. See Table 1 for key interatomic distances and angles in crystal structures of 1 versus 2.

In our attempts to widen the alkene-alkene distance and functionalize the bottom face of the pro-cleft structure 1, we found that 1 was unusually resistant to carbonyl functionalization. For example, diketone 1 was resistant to reduction with sodium borohydride, but did react slowly with lithium aluminium hydride in tetrahydrofuran under reflux, with 75% conversion to 2 after 24 h (Scheme 1). Diketone 1 was also highly resistant to attack from methylmagnesium iodide in refluxing diethyl ether (≤ 5% yield). The direct use of alkyllithiums in ketone a-deprotonations is usually avoided due to their substantial nucleophilicity. Instead, a-deprotonations are typically effected at low temperature with weaker bases, such as lithium diisopropylamide generated from alkyllithiums. However, the carbonyl groups of 1 were resistant to nucleophilic attack by methyllithium in refluxing diethyl ether over 2 h. When mixtures of alkyllithiums, alkyl halides and 1 were refluxed in diethyl ether, alkylation occurred at all four positions alpha to the carbonyl groups and to the lower face to give 6 (58 %; 87 % per methylation, 16 h) and 7 (77 %; 94 % per alkylation, 72 h) (Scheme 2). Similarly, treating 1 with excess methylmagnesium iodide and methyl iodide in tetrahydrofuran also led to exclusive tetramethylation (6, 47 %). All a-alkylations of 1 with b-hydrogen containing electrophiles failed due to faster electrophile degradation via base mediated elimination, consistent with the a-protons of 1 being only weakly acidic. Further, these highly congested products were formed in high yields, with no observed formation of the less hindered O-alkylation products. Together, these results suggest that a-deprotonation of 1 yields carbanion resonance structure 4, with very little ring rehybridization to the enolate 5, in order to preserve the favourable p-p interaction.

OHOHR

Ror MeLior MeMgI

H H

OO

H H

1 2, R = H (75%)3, R = Me (< 5%)

LiAlH4

C...C distanceO...O distance

H...Hdistance

[a] Dr. M. J. Stoermer, Dr, W. A. Wickramasinghe , Dr K. A. Byriel, Dr J. Y. W. Mak, Prof. D. P. Fairlie* Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072, Queensland, Australia Fax: +61 7 3346 2989 E-mail: d.fairlie@imb.uq.edu.au

[b] Dr. D. C. R. Hockless, Assoc. Prof. B. W. Skelton, Dr. A. N. Sobolev, Prof. A. H. White School of Chemistry and Biochemistry University of Western Australia, Perth, 6009, Western Australia, Australia

# Deceased March 2016

(Supporting information for this article is available on the WWW under http://www.chemeurj.org/ or from the author.)

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Scheme 2. Alkylation of 1 primarily occurs alpha to the carbonyls to produce 6 and 7, with a-deprotonation to 4 proceeding with little tautomerization to O-enolate 5, consistent with the ring rehybridization from sp2 to sp3 weakening the alkene-alkene p-p interaction.

The resistance of 1 to alkylation at the carbonyls can be contrasted with the reactivity of its diastereomer 8, in which the olefins are on separate faces. Compound 8 has recently been alkylated with allylmagnesium bromide at room temperature to give 9 in 85 % yield (Scheme 3).[8] The lower face of 8 is even more sterically hindered than in 1 and yet was readily alkylated, supporting the idea that the stereoelectronic properties of 1 disfavour rehybridization of the carbonyl group. Separation of the alkenes likely removes the favourable p-p interaction in 1 and introduces an unfavourable clash between the negatively charged oxygen and the p cloud. Both factors may contribute to a higher energy rehybridization transition state for 1 than for 8.

Scheme 3. Nucleophilic addition of allylmagnesium bromide to diketone 8, a diastereoisomer of 1 with more steric congestion at the carbonyl centres.8

The crystal structures of 1, 2 and 6 provided a valuable comparison of their key structural features (Supporting information, Figure S1-S5, Table 1). The alkene-alkene separation distance in 1 (4.26 Å) supports considerable p-p orbital overlap, suggesting that reactivity of each alkene would be influenced by the other. On the other hand, sp2 to sp3 rehybridization in the cyclohexadione core from 1 to 2 brought the oxygen atoms 2.18 Å closer to one another (Table 1), and created a hydrogen bond between the hydroxyls to form a partition between the two alkenes (Supporting Information, Figure S2). Furthermore, this rehybridization caused a substantial increase in the alkene-alkene separation by 1.25 Å, supporting little p-p interaction between the more isolated alkenes of 2. In contrast, the steric effect of tetramethylation in compound 6 reduced the alkene-alkene distance to 3.71 Å. The central cyclohexanedione core was flatter, as shown by an

increase in the O…O distance to 5.08 Å and a reduction in the angle between the carbonyls and the ring to 24.1°.

Table 1. Key interatomic distances and angles from crystal structures[a] for compounds 1, 2 and 6 (Scheme 1 describes distances referred to below)

Parameter 1 2[b] 6

Alkene-alkene C…C distance (Å) 4.26 5.51 3.71

O…O distance (Å) 4.90 2.72 5.08

Axial H…H distance (Å) 2.97 2.46 3.46[c]

C-O bond to 6-membered ring plane angle Φ (deg) 31.3 91.2 24.1

[a] Crystal structure data for 1, 2 and 6 in Supporting Information. [b] Average of 6 distances in unit cell. [c] C…C distance (Å) between the corresponding axial methyl groups.

We anticipated that p-p orbital overlap between the proximal olefins would affect their Diels-Alder reactivities. To investigate this, we compared the [4+2] cycloaddition reactions of 1,3-diphenylisobenzofuran (dpibf, 10) with 1 versus 2 (Scheme 4), monitoring the reactions by 1H NMR spectroscopy (Figure 1).

Scheme 4. Successive Diels-Alder cycloadditions of 1,3-diphenyl-isobenzofuran (10) with the twin dienophiles of 1 and 2 in chloroform at 80 °C.

For the reaction of 1 with 10, assuming that the stepwise cycloaddition to 11 and then 12 was first order with respect to each olefin and 10, the first cycloaddition to give 11 had a rate constant of k1 = 1.6 ´ 10-2 M-1s-1 (CDCl3, 80 °C), or k1 = 8.0 ´ 10-

3 M-1s-1 taking into account that each molecule of 1 had two equivalents of olefin. However, the second addition from 11 to give the cleft-like structure 12 was significantly slower (k2 = 3.3 x 10-3, CDCl3, 80 °C). The reaction was highly stereoselective, giving almost exclusively the exo/exo product (>95 %),

O

O

OHOH

THF, 0 °C to rt, 5 h, 85 %

98

MgBr

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OHOH

OO

OPh

PhO

Ph

Ph

OHOHO

Ph

Ph

OHOHO

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PhO

Ph

Ph

k1

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4.26 Å 5.51 Å

k2

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OPh Ph

10

10 10

1010

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OO

H H1

OO

4

O

Osp2

5

R R

OO

R R6, R = Me (58%)7, R = BOM (77%)

R-I, Et2O,reflux

MeLi, Et2O, reflux

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indicating that approach of the second molecule of 10 to intermediate 11 was not hindered by the first formed dpibf. Diol 2, with a larger alkene-alkene separation than 1, reacted more slowly with 10 to give 13 (k3 = 2.3 ´ 10-3 M-1s-1, CDCl3, 80 °C; or k3 = 1.2 ´ 10-3 M-1s-1 factoring in two equivalents of olefin in 2). The rate constant for the second addition to give 14 (k4 ~ 1.3 ´ 10-3 M-1s-1) was similar to the first. The final adduct was also almost exclusively exo/exo (> 95 %), ruling out the possibility that the hydroxyl groups or the first dpibf addition sterically hindered the second addition. Together, these results suggest that a proximal olefin had accelerated the Diels-Alder cycloaddition of 1 with 10, relative to 2 with 10.

Figure 1. Formation of 11 (filled squares) and 12 (filled circles) from 1 and 10, and formation of 13 (open triangles) and 14 (half open squares) from 2 and 10, as monitored by 1H NMR spectra. Initial concentrations of 1, 2 and 10 were 1, 1, and 2 M, respectively.

Next, we used computer modelling to provide a mechanistic rationale for these observed rate differences in formation of 11 and 13. Firstly, we used semi-empirical, ab initio and force field based methods to create three-dimensional models of the pro-cleft compounds 1 and 2 that were consistent with their crystal structures (Supporting information, Table S1, Figures S6-S7). Having validated these methods, LUMO energies for dienophiles 1 and 2 were calculated semi-empirically.[9] Consistent with olefin cooperativity and the kinetic data, the LUMO energy of 1 (0.73 eV) was lower than for 2 (1.02 eV), while both were lower than for norbornene (1.28 eV). The LUMO energy of 1 was comparable to that of norbornene bearing an electron-withdrawing bromine substituent (0.71 eV).[9] These calculations suggest that the rate acceleration observed in the Diels-Alder reaction was due to a lowering of the LUMO energy by the nearby olefin in 1 versus 2. AM1 molecular models[9] of the products 12 and 14 were calculated and compared (Figure 2). The AM1 models showed that the cleft of 12 was too small to accommodate a guest molecule, but the ring rehybridization in 14 was predicted to widen the cavity to permit solvent access. We sought to confirm these structural predictions by X-ray diffraction and grew

crystals of 12 and 14 from chloroform/cyclohexane. Crystals of 12 unfortunately decomposed before sufficient diffraction data could be collected, but a crystal structure of 14 could be obtained and it validated the AM1 structure showing a cleft-like structure (Figure 3). Intriguingly, two molecules of disordered cyclohexane solvent were found trapped in the crystal lattice near to, but not wholly inside, the cleft in 14 (Figure 3).

Figure 2. Solvent accessible surfaces of 12 (left, AM1 model), 14 (middle, crystal structure) and 15 (right, crystal structure). 12 had an occluded cleft, whereas 14 and 15 had solvent accessible clefts.

Figure 3. Crystal structure of 14 with two disordered cyclohexane molecules. Ellipsoids are shown at 20% probability.

These findings encouraged us to derive another cleft structure from 14. We reacted 14 with hydrochloric acid to produce the smaller bis-naphthyl derivative 15 (Scheme 5). The AM1 model predicted that 15, like its precursor 14, would have a solvent exposed cleft with a similar ring separation at the top of the cavity but a different cavity shape. A crystal structure for 15 (Figure 2, 4) validated AM1 predictions. The naphthyl and template planes were roughly perpendicular to one another. The four pendant phenyl rings were sterically enforced in a perpendicular arrangement relative to the naphthyl rings, further encroaching on cavity space. Interestingly, one molecule of chloroform was found trapped within the cavity and directly bound to components of 15. This guest capture was underpinned by an unusual interaction between one of the naphthyl p systems and the chloroform hydrogen, an example of an unusual weak hydrogen bond interaction between p-electrons and polar hydrogen bond donors.[10] At ~2.5 Å, this is considerable shorter than the distance ~2.8 Å typically reported[11] for this type of interaction. Two of the chlorine atoms

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contacted (2.8 – 3.0 Å) the ortho hydrogens of the two pendant phenyls on the opposite cleft face. Similar to 12, an intramolecular hydrogen bond between the hydroxyls was suggested by the electron density difference map.[12] In summary, 15 is a molecular cleft capable of accommodating a small guest molecule and, in this case, makes interactions with three of the four exposed atoms of the guest.

Scheme 5. Dehydration of 14 with hydrochloric acid to give molecular cleft 15.

Figure 4. Crystal structure of 15, with one molecule of chloroform bound in the cleft. Ellipsoids are shown at 20% probability.

In conclusion, the non-conjugated diene 1, a formal Diels-Alder adduct of cyclopentadiene and 1,4-benzoquinone, is an architecturally promising scaffold for the construction of molecular clefts. This study has demonstrated that functionalization and hybridization of the central cyclohexanedione profoundly alters the separation between the alkenes, and that this separation influences reactivity of each olefin in cycloaddition reactions with dienes. With the alkenes of 1 positioned parallel to the scaffold plane, it is pre-organized, via Diels-Alder cycloaddition reactions, to fashion U-shaped structures (e.g. 14, 15), potentially capable of accommodating guest molecules. While p-p interactions are known to be important in non-covalent processes such as ligand-protein binding, their effects on chemical reactivity have been less studied. Here, we have shown computationally and structurally that the closely approaching alkenes in 1 influence their reactivity as dienophiles, as well as the structural rigidity of the scaffold. These findings support other studies where the reactivity of isolated olefins is affected by p-p interactions.[4-7]

Lastly, we describe the capacity of this highly constrained scaffold to generate rigid molecular clefts by synthesizing 14 and 15, with the crystal structure of the latter showing a molecule of chloroform bound entirely within the cavity. Together, these findings highlight stereoelectronic properties that influence Diels-Alder cycloaddition chemistry and suggest new potential applications to host-guest chemistry for the future. Experimental Section

All experimental data is shown in the Supporting Information. CCDC-745259 (compound 1), CCDC-746776 (compound 2), CCDC-1530046 (compound 6), CCDC-745260 (compound 14), and CCDC-745261 (compound 15) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data%5Frequest/cif.

Acknowledgements

We thank the Australian Research Council for funding.

Keywords: diene • cavity • host-guest systems• solid-state structures • pi interactions

[1] (a) J. Rebek, Jr. Acc. Chem. Res. 2009, 42, 1660-1668. (b) E. Biavardi, M. Favazza, A. Motta, I.L. Fragalà, C. Massera, L. Prodi, M. Montalti, M. Melegari, G.G. Condorelli, E. Dalcanale, J. Am. Chem. Soc. 2009, 131, 7447-7455. (c) D.J. Cram, Nature 1992, 356, 29-36.

[2] M.J. Stoermer, D.N. Butler, R.N. Warrener, K.D.V. Weerasuria, D.P. Fairlie, Chem. Eur. J. 2003, 9, 2068-2071.

[3] G. Mehta, S. Padma, J. Am. Chem. Soc. 1987, 109, 7230-7232 [4] R. Gleiter, L.A. Paquette, Acc. Chem. Res. 1983, 16, 328-334. [5] M.J. Goldstein, R. Hoffmann, J. Am. Chem. Soc. 1971, 93, 6193-6204. [6] S. Kammermeier, H. Neumann, F. Hampel, R. Herges, Liebigs Annalen,

1996, 1795-1800. [7] P.R. Ashton, G.R. Brown, N.S. Isaacs, D. Giuffrida, F.H. Kohnke, J.P.

Mathias, A.M.Z. Slawin, D.R. Smith, J.F. Stoddart, D.J. Williams, J. Am. Chem. Soc., 1992, 114, 6330-6353.

[8] S. Kotha, O. Ravikumar, Beilstein J. Org. Chem., 2015, 11, 1259-1264. [9] Structures were energy minimized and HOMO/LUMO energies

predicted using the AM1 method in Mopac. [10] (a) L.F. Newcomb, T.S. Haque, S.H. Gellman, J. Am. Chem. Soc. 1995,

117, 6509-6519 and references therein. (b) S. Suzuki, P.G. Green, R.E. Bumgarner, S. Dasgupta, W.A. Goddard III, G.A. Blake, Science 1992, 257, 942-945. For examples of weak H-p interaction in host-guest recognition see: (c) S. Tsuzuki, A. Fujii, Phys. Chem. Chem. Phys. 2008, 10, 2584-2594. (d) M. Nishio, CrystEngComm, 2004, 6, 130-158. (e) M. Nishio, Y. Umezawa, M. Hirota, Y. Takeuchi, Tetrahedron, 1995, 51, 8665-8701.

[11] For example: (a) K. Kobayashi, Y. Asakawa, Y. Kikuchi, H. Toi, Y. Aoyama, J. Am. Chem. Soc. 1993, 115, 2648-2654. (b) J.F. Stoddart, in Host-Guest Molecular Interactions : From Chemistry to Biology, Ciba Foundation Symposium, Wiley, New York, 1991, 158, 5-22. (c) G. Desiraju, A. Gavezzotti, Acta Cryst. 1989, B45, 473-482 and references therein.

[12] This arrangement is similar to that observed in resorcarene cavitands, where two neighbouring host OH groups engage in hydrogen bonding to one another and to guest alcohols. See (a) Y. Tanaka, Y. Aoyama, Bull. Chem. Soc. Jpn. 1990, 63, 3343-3344. (b) Y. Kikuchi, Y. Kato, Y. Tanaka, H. Toi, Y. Aoyama, J. Am. Chem. Soc. 1991, 113, 1349-1354.

OHOH

15

OHOHO

Ph

PhO

Ph

Ph

14

PhPh

PhPh

- H2O

HCl

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Entry for the Table of Contents

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Stereoelectronic effects: Five crystal structures show that structural rigidity and pi-pi interactions strongly influence Diels-Alder [4+2] cycloadditions leading to U-shaped clefts, one of which captures a chloroform molecule within its aromatic enclave.

Martin J. Stoermer, Wasantha A. Wickramasinghe, Karl A. Byriel, David C. R. Hockless, Brian W. Skelton, Alexandre N. Sobolev, Allan H. White, Jeffrey Y. W. Mak, David P. Fairlie*

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Stereoelectronic effects on dienophile separation influence the Diels-Alder synthesis of molecular clefts