Bridging and Conformational Control of Porphyrin Units through Non‐Traditional Rigid Scaffolds

Abstract Connecting two porphyrin units in a rigid linear fashion, without any undesired electron delocalization or communication between the chromophores, remains a synthetic challenge. Herein, a broad library of functionally diverse multi‐porphyrin arrays that incorporate the non‐traditional rigid linker groups cubane and bicyclo[1.1.1]pentane (BCP) is described. A robust, reliable, and versatile synthetic procedure was employed to access porphyrin‐cubane/BCP‐porphyrin arrays, representing the largest non‐polymeric structures available for cubane/BCP derivatives. These reactions demonstrate considerable substrate scope, from utilization of small phenyl moieties to large porphyrin rings, with varying lengths and different angles. To control conformational flexibility, amide bonds were introduced between the bridgehead carbon of BCP/cubane and the porphyrin rings. Through varying the orientation of the substituents around the amide bond of cubane/BCP, different intermolecular interactions were identified through single crystal X‐ray analysis. These studies revealed non‐covalent interactions that are the first‐of‐their‐kind including a unique iodine‐oxygen interaction between cubane units. These supramolecular architectures indicate the possibility to mimic a protein structure due to the sp3 rigid scaffolds (BCP or cubane) that exhibit the essential conformational space for protein function while simultaneously providing amide bonds for molecular recognition.


Introduction
Definedm olecular architectures are ap rerequisite for the logical construction of multifunctional chemical systems. In carbon-based covalent systems the individual effector units are typicallyl inked by either conjugating sp-or sp 2 -hybridized units or by flexible sp 3 -hybridized bridges.T he use of short, robust, and spatially defined aliphatic linker units opens new avenues with their potential application as molecular isolators, resistors and rigids caffolds, alongside the benefit of their inherentmaterials properties.
Synthetic chemists are continually seeking to prepare new rigid multi-porphyrin architectures due to their potentiala pplications as organic conducting materials, near-infrared( near-IR) dyes, nonlinear optical materials, and molecular wires. [1] A number of synthetic strategies have been employed to access these multi-porphyrin arrays using approaches such as:(a) connectingt he porphyrin units via phenylene, ethynyl, ethenyl or alkane linkers [2] or (b) connectingt wo or more meso-mesolinked porphyrin units via oxidative fusing reactions. [3] However,m ost of the porphyrin arrays reported have problemss uch as poor solubility,s ynthetic inaccessibility,a nd conformational heterogeneity.I nmeso-meso-linkedp orphyrin arrays, the porphyrin units are orthogonal to one another which can cause a significant energy/charge sink. Furthermore, porphyrin arrays joined directly by p-conjugated linkers exhibit significantly altered UV/Vis spectra, indicating very stronge lectronic coupling, that is, loss of the characteristico fi ndividual units due to delocalization of p-electrons. Hence, it is necessary to design am olecule which can predictably exhibit ad esired energy-and/ore lectron-transfer process that is achievable withoute ffecting electronic delocalization and/ora ne nergy sink. [1][2][3] Astraightforward strategy for avoiding any undesirable overlap of the p-systems may be to attach two porphyrin skeletons through non-traditional rigid scaffolds such as bicyclo [1.1.1]pentane (BCP) or cubane. These saturated entities are transparent to UV/Vis light and exhibit specific three-dimen-sional (3D) arrangements of the bridgehead carbons. This positions the chromophoricu nits in ar igid and linear fashion without any electron delocalization or conjugation such as to potentially reduce the drawbacks previously outlined. [4] Herein, we report the first synthesis of porphyrin dimers that utilize either BCP or cubane as ar igid linear scaffold ( Figure 1). This library of BCP/cubanep orphyrin arrays contains some of the largest non-polymerics tructures available for cubane and BCP.
1,4-Disubstituted cubane is aw ell-known bioisostere of para-substituted phenylene rings due to the similar distance across the cube body diagonal of 2.72 vs. 2.79 for ab enzene ring. [5] BCP is the smallest member of the bicyclic alkane family,i nt erms of actual size rathert han in terms of atoms present.I ndeed,B CP exhibits the shortest non-bonded distance between bridgehead carbon atoms of 1.85 ,w hich is closer in bond length to ethyne ( 1.20 ). [6] The 3D, compact, electronically isolating, ands aturated structures of cubane and BCP enablet hem to avoid undesirable p-p stacking which may lead to improved solubility of chromophoric arrays. Despite their desirable well-definedd imensions andr igid-rodg eometries, the chemistryo ft hese moieties is undeveloped, particularlyi nt erms of functionalization or CÀH-activation at the bridgehead carbons. [7] BCP and cubane are transparentt oU V/Vis light and most often their application is restricted to bioisosteres [8] and crystal engineering. [9] The structuralp re-organization and high thermal stability of these compounds make them attractive candidates by which to link two chromophoric units,b ut their use has been neglected so far. [7a, 10] The limited use of these nontraditional scaffolds is due to perceived complex synthetic procedures and limited commercial supply chain of precursors. In addition, appending rigid sp 3 linkers as connectors between two chromophoric units is synthetically demanding.
Recent synthetic developments by Baran,A ggarwal and ourselves include methods based on decarboxylative sp 3 CÀCc oupling to functionalize the bridgehead carbonso fc ubane and BCP. [11] Knochel and co-workersh ave also reported an efficient methodt os ynthesize 1,3-bisaryl substituted BCPs. [12] Additionally,a mide bonds have been introduced at the bridgehead carbons of cubane and BCP, [13] however most of these reported moieties were used as bioisosteres [8] or in crystal engineering. [9] Yet, thesec ompoundsa lso have the potential to be utilized as molecular building blocks. Moreover,c ubane/BCP could be implemented as rigid scaffolds linkingt wo chromophores while providing as ynthetic handle for molecular recognitiono fs mall molecules or ions.
Buildingu pon the progressm ade in synthetically accessing these non-traditional rigid scaffolds, we envisioned appending BCP/cubane between two porphyrin units in ac onformationally controlled manner. The utilizationo fs emi-rigid amide bonds for the attachment of ap orphyrin skeleton to ar igid scaffold introduces ac ontrolled conformational flexibility into porphyrin dyad(s). This allowss ignificant modulation of the photophysical properties in the porphyrin dyad(s) through the coordination of transition metal(II) ions ( Figure 2). By varying the distance and angles between the two chromophores it is hoped that the extent of the impact that cation coordination has on the photophysical properties of am ulti-chromophoric tweezer-like system can be investigated.
As cubane andB CP are rigid and relatively inert scaffold, the amide bonds are the only variable in the system and at rue measurement of their role in the conformational changes can thus be undertaken. We herein present porphyrin units bridgedt hrough non-traditional BCP/cubanec onnectors as a test case for multichromophoric and/ore lectroactives ystems in general.

Synthesis and characterization
The amide bond is crucially important as one of the main chemicall inkagesf ound in biologically and pharmaceutically active compounds. [14] Amideb onds exhibit ap lanar trans configuration of the NÀHa nd C=Om oieties and undergo very little rotation or twisting around the bond due to amido-imido tautomerization. The semi-rigid nature of amide bonds enables conformational control over the molecular architectureo ft he compound they are part of courtesy of hydrogen bonds and the coordination of metal ions (Figure 2). To this end, the synthetic design of the current project focused on the functionalization of the bridgehead BCP/cubane carbons through amide bonds. Firstly,w es tarted with the synthesis of small rigid buildingb locks. Carboxylic acid derivatives of cubane (1 and 2) were reacted [15] with substituteda ryl amines 3-12 to access the amide derivatives 13-29.T he use of HATU/HOAt as an activating agent in presence of DIPEA in DMF at 25 8Cp rovided the mosts uitable synthetic reactionc ondition by which to access amide substituted cubanes (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).
To demonstrate the potentialv alue of this method, we next examined the scope of meso-amine-substituted porphyrins in amide coupling reactions with cubane 1 and 2.5 -(4'-aminophenyl)-10,15,20-triphenylporphyrin (7)a nd its zinc(II) complex (8)w ere synthesized by mono-nitration of TPP followed by reduction using procedures reported in the literature. [16] Ta ble 1o utlines the different reaction conditions employed to optimize the amide coupling reaction between 1 and 7.T he use of HATU/HOAt in presence of DIPEA furnished the amidecoupled cubane-porphyrin array 21 in 79 %isolated yield. However,t he use of other activating agents such as DIC and ethylchloroformatei nt he presence of TEAo rD MAP also resulted in the formation of product 21,a lbeit in lower yields of 43 %a nd 31 %, respectively ( Table 1). Reaction of porphyrin 8 with cubane 1 showst he neat conversion of porphyrin 8 into the cubane porphyrin array 19 in 52 %y ield.
Notablec ompounds 19 and 21 were subjected to further functionalization. Base hydrolysis of zinc and free base substituted porphyrin 19 and 21 yielded the carboxylic acid derivatives of cubane-porphyrin array 20 and 22 respectively,i n quantitative yields. Similarly,t he reaction of cubane-1,4-d icarboxylic acid (2)w ith 7 and 8 resulted in access to the very first porphyrin-cubane-porphyrin arrays 25 and 26,r espectively. Next we attempted the synthesiso fZ n II -porphyrin-cubanefree base porphyrin array 27 via amide coupling reaction of amine substituted porphyrin 7 and carboxylic acid substituted cubane porphyrin 20.U se of optimizedr eactionc onditions resulted in unsymmetric dimer 27 in a5 5% yield.
The successful functionalization of cubane motivated us to next attemptf unctionalization of the BCP using the same amide coupling method. However,i nitial attempts to synthesize the required BCP building blocks using HATU/HOAt, EDC, or DIC were unsuccessful. This may be due to unstableB CP intermediates capable of undergoing rearrangement to result in ring-opened moieties. The BCP carboxylic acid was insteadr eacted with (COCl) 2 /TEA, followed by the desired amine. Initially, this reaction was conducted at room temperature similart o the cubane analogues above,however,this was met with limited success as the product was detected only in as mall amountsb y 1 HNMR spectroscopy and mass spectrometry.T his limited success was mitigated by the use of an elevated reaction temperature of 40 8Cf or both steps, which resulted in a significant increase in the product yields (49-77%)( Scheme 2). The crude reactionm ixtures werep urified via recrystallization using as malla mount of CH 2 Cl 2 and excessh exane to access the desired products as white powders. The reaction of BCP 30 with aniline 3 and 4 resulted into the formation of 32 and 33 in 57 %a nd 61 %y ield. Next, the meta-phenyl substituted BCPs 34 and 35 were synthesized via amide coupling reaction of BCP 30 and aniline 5 and 6,r espectively.A mide coupling of BCP 31 and anilines 3-6 resulted into the formation of amide substituted BCPs 36-39.W eh ad found that the amide coupling reactions proceed optimally with meta-/para-substituted aniline in presence of (COCl) 2 /TEA. Unfortunately,a mide coupling with ortho-substituted anilines resulted in degradation. The ineffective ortho-substituted aniline coupling mayb e causedb yt he proximity of the amine and iodo/ethynyl groups,e nabling H-bonding interactions between the moieties, ultimately reducing the basicity and reactivity of the amine. On the other hand, the cubane porphyrin dimer 29 was accessed in a5 0% yield due to the replacement of the small H-bonding moieties with ap orphyrin, preventing the reduced amine basicity.
UV/Vis spectrao ft he chromophore arrays were recorded in CHCl 3 or THF at room temperature. The free base dimers 26 and 51 illustrate at ypical etio-type porphyrin spectrum, havingt he Soret and four Q-bands in decreasing intensity.T he symmetrical zinc dimers 25, 28, 29, 50, 52,a nd 53 showeda n absorbance maximum at 422 nm. The full width at half maxima( FWHM) of thesed imers is nearly equal to 5,10,15,20tetraphenylporphyrin (H 2 TPP) or its zinc(II) complex (ZnTPP), displaying no evidence of excitonc oupling betweent wo porphyrin units, which supports the suggested potential trans conformation of one porphyrinu nit with respectt oa nother unit. [22] The absorption spectra of ethynyl-linked porphyrin dimers such as 28, 29,a nd 53 exhibited a1 5-18 nm bathochromic shift compared to the phenylene-linked dimers 25 and 50 due to the p-extended ethynylorp henylethynyl moieties. The UV/Vis spectra of ethynyl-linked dimers (28, 29,a nd 53)e xhibit nearly the same FWHM and l max as compared to the precursor amine porphyrin (11 and 12). Similar l max values of monomers and dimers indicatet he lack of throughs pace or through bond electronic communication between porphyrin units, that is, a trans orientation of the synthesized dimers.
The crystal structures of BCP 33, 35,a nd 38 exhibit non-covalent interactions between amide N-donors and C=Oa cceptors within the crystal lattices. The natureo ft hese interactions is dependentu pon the substitution pattern at the phenylene ring. The crystal structure of para-substituted BCP compound 33 reveals repetitive head-to-head N1···O1=Ch ydrogen-bond interactions at distances of 2.970 (Figure 4). In contrast to 33,t he crystal structure of meta-substituted BCP 35 exhibits head-to-tail N1···O2=Ci nteractions at distances of 3.061 , leadingt ot he formation of an on-covalently attached inver-sion-centered dimer (Figures S138 and S139 in Supporting Information).
Similarly,t he crystal structure of bis-meta-substituted BCP 38 shows head-to-tail interactions at distances of 2.910 and forms as upramolecular 3D network/array ( Figure S141 in Supporting Information).
In nature, the 3D structures of proteins and other biomolecules are controlled using H-bonding interactions between trans NÀHa nd C=Om oieties of amino acids and these 3D architectures are responsible for their specific biological functions. Thes ubstituents surrounding the amide bondsd irect the non-covalent interactions in all of the above-mentioned crystal structures, and this indicates the possibilityo fp otentially mimicking protein architecture with sp 3 rigid scaffolds (BCP or cubane). This would provide the conformational space essentialf or protein function, whiles imultaneously providing amide bonds for "substrate" coordination.
The crystal structure of the BCP-porphyrin 46 illustrates the planarc onformation of the macrocyclic core while the crystal packing of this molecule furthers hows intermolecularh ead-totail non-covalent D···A interactions between the acceptor Zn II metal of the porphyrin and donor oxygen atom of the carbonyl group in the amide moiety at ad istance of 2.191 ( Figure 5). This particulari nteraction supports the proposed mechanism of binding between at ransition metal(II) and the C=Om oiety of the amide bond (vide infra). Similarly,t he crystal structure of [5-(2'-aminophenylacetylene)-10,20-bis(4'-methylphenyl)-15-phenylporphyrinato]zinc(II) (12)a lso exhibits   head-to-tail D···A interactions, in this case between the donor N-atom of the amineg roup from one porphyrin to the Zn II center of another ( Figure S145 and S146 in the Supporting Information).T his interaction is further supported by 1 HNMR spectra where the ortho-amine protons resonate at À0.58 ppm due to the shielding effect of the porphyrin ring current.
Along with the above mentioned non-covalent interactions, we also observedau nique exampleo faporphyrin-based ion pair complex,t hat is, ap air of opposite charges held together by Columbic interactions in the same solvent-shell. [26] Although charge-separated ion pair complexes are quite common in transition-metal organometallic chemistry,i on pair complexes of phlorins and porphodimethene-based systemsa re also known,t his type of interaction hasn ot previously been observed for systems with intact porphyrin cores. [27] The crystal structureo fp orphyrin 45 is unique as it exhibitsa ni on pair interaction between an axial chloride ligand and a[ Et 3 NH] + counter ion in the same unit cell withoutd isturbing the aromatic 18p-electronp athway ( Figure 6). Axial coordination results in displacemento ft he Zn II ion from the 24-atom mean plane by 0.51 .T he chloride and triethylammonium ions exhibit an ion pair interaction at ad istance of 3.043 .T his is further supported by the 1 Ha nd 13 CNMR spectra of compound 45 where the ratio of the porphyrin derivativea nd [Et 3 NH] + was found to be 1:1. To best of our knowledge, it is the first example of ap orphyrin-based charge-separated ion pair complex. Figure 6i llustrates an example of the [Et 3 NH] + [porphyrin(ZnCl)] À ion pair in whichanegatively chargedp orphyrin electrostatically interacts with positively charged triethylamine. In the crystal structure of 45,Z n II binds to the Cl À and the oxidation state of the Zn metal ion remains unchanged,t he chloride ion shows noncovalent interaction with [Et 3 NH] + .M ost of the reported examples of chloride coordinated Zn II porphyrinoids either fall into the class of 16 p electron macrocycles or N-substituted porphyrins. [27] In the case of Nsubstituted porphyrins, the negative charge of the chloridei s counter-balanced by the positive charge on the tertiary core-N-atom whereas in present case chargei sc ounter-balanced by [Et 3 NH] + and the porphyrin core remains intact making this an uniquee xample.
Structure elucidation of BCP-porphyrin 45 revealed the nearly coplanarn ature of the BCP-appended arm with respect to the porphyrin plane. In contrast, BCP-porphyrin 46,w hich has al arger distance betweent he BCP and porphyrin moieties, showed orthogonal rotation of the phenylr ings with respect to the porphyrin plane. Hence, 45 and its analogues show more promise towards the synthesis of cubane/BCP-linked porphyrins ystems for electron/energy studies owing to their extendedc onjugation.

Conclusion
We have designed, synthesized,a nd characterizedb ridgehead substituted bicyclo[1.1.1]pentanea nd cubane derivatives via amide coupling reactions. This work demonstrates ab road substrate scope with over 35 new derivatives of cubane/BCP that were synthesized in moderate to good yields. The single crystal X-ray structures of small rigid linker motifs (13,33,35, and 38)r evealed supramolecular 3D networks with combined and repetitive inter-and intramolecular H-bonding interactions. Significantly,t he crystal structure of cubane 13 showed an unusualC =O2···I1 interaction alongw ith the usual N1···O1= Ci nteraction to result in a3 Dc age-like structure. The formation of 3D supramolecular network dependento nt he structurally pre-organized BCP/cubane scaffold in association with the semi-rigid amide moieties.
The crystal structure of porphyrin 45 illustrates au nique example of porphyrin based ion-pair complex. Additionally,p orphyrin 46 exhibits non-covalent D···A interactions between the acceptor Zn II metal of the porphyrin and the donoro xygen atom of the carbonyl group in the amide moiety in solid-state. Af ollow-up study on selectived etection of small molecular motifsv ia this type of arrays is underway and will be reported separately.

Experimental Section
General information, instrumentation, synthesis of precursors, crystallographic studies, and complete synthetic details of all synthesized compounds are given in Supporting Information.
General procedure 3tosynthesize meso-ethynylamine substituted porphyrins 9-12:I odo porphyrin (1.0 equiv) was placed in an oven-dried Schlenk flask and heated under vacuum. The reaction flask was purged with argon and am ixture of THF/NEt 3 (3:1) was added. Argon was bubbled through the solution for 15 min then ethynylaniline (5.0 equiv), PdCl 2 (PPh 3 ) 2 (0.15 equiv) and CuI (0.3 equiv) were added. The reaction mixture was heated to 70 8C and allowed to stir for 4h.T he reaction mixture was diluted with CH 2 Cl 2 (10 mL) followed by removal of solvents in vacuo. Crude reaction mixture was purified by silica gel column chromatography.
General procedure 4f or Sonogashira cross-coupling using meso-ethynyl porphyrin:A no ven-dried Schlenk tube charged with ethynyl porphyrin (1.0 equiv) and iodo-substituted cubane or BCP was heated under vacuum. THF (5 mL) followed by NEt 3 (2.5 mL) were added to reaction vessel. Argon was bubbled through the solution for 10-15 min. and PdCl 2 (PPh 3 ) 2 (0.2 equiv) and CuI (0.3 equiv) were added. The resulting reaction mixture was heated at 40 8Ca nd progress of the reaction was monitored by TLC. Reaction mixture was filtered through aC elite pad. Solvent was evaporated in vacuo, crude reaction mixture was purified by silica gel column chromatography.
General procedure 5f or Suzuki cross-coupling:T oa no ven-dried Schlenk tube charged with porphyrin (2.1 equiv), BCP linker (1.0 equiv) and K 3 PO 4 (10.0 equiv) anhydrous DMF (5 mL) was added under inert atmosphere. The above solution was purged with argon for further 15 min followed by addition of 0.2 equiv of Pd(PPh 3 ) 4 .T he reaction mixture was heated to 100 8Ca nd allowed to stir for 18 h. The solvent was removed in vacuo, crude reaction mixture was dissolved in CH 2 Cl 2 washed with NaHCO 3 followed by brine. Organic layer was extracted with CH 2 Cl 2 .E xtracted organic phases were combined and solvent was evaporated. The resulting crude reaction mixture was purified by silica gel column chromatography.