Structural Effects of meso-Halogenation on Porphyrins: meso-Xn-ABCD Macrocycles

The use of halogens in the crystal engineering of porphyrin scaffolds has been a topic of strong interest over the past decades. Previously, this was focused on the introduction of a variety of halogens on the meso-phenyl groups of the porphyrin. However, investigations into the effects of direct halogenation of porphyrins at the meso-position on their crystalline architectures have not been conducted to date. Herein we have characterized a series of direct meso-halogenated porphyrins using single crystal X-ray crystallography. This is accompanied by a detailed conformational analysis of all deposited meso-halogenated porphyrins in the CCDC. In this study we


Introduction
Crystal engineering using porphyrins as a scaffolding unit has been a topic of increasing interest over the past few decades. The first instance of this began with the seminal work of Byrn et al. proposing the idea that the highly ordered "porous" structure of porphyrin clathrates can be used as a form of "porphyrin sponge" [1]. This work described the use of a 5,10,15,20-tetraphenylporphyrin 'host' to trap a variety of solvent 'guest' within the crystal lattice, using strictly hydrogen-bonding and van der Waals forces. Since then, crystal engineering of porphyrins has focused on the use of a variety of noncovalent interactions such as hydrogen-bonds and halogen-bonds, or metal coordination interactions [2−13]. These complexes have been reported to be of use in a range of areas in material sciences, such as molecular sieves, due to the formation of a three-dimensional lattice in which more than 50% of the crystal volume consisted of open straight channels [5,6]. For example, one notable report is that by Titi et al. on the self-assembly of meso-tetraaryl porphyrins through halogen bonding forming a chiral architecture based on C−I···N and C−I···π interactions [7].
In recent years there has been a strong uprising interest for substituting hydrogenbonding motifs with their halogen-bonding counterparts. This is due to their relative versatility in areas such as directionality, the tenability of the σ-hole, hydrophobicity, and donor atom size [14]. These traits allow for the design of novel supramolecular architectures which are directive and reproducible, without relying on the hydrogenbonding functionality which in some cases can be undesirable. Recent studies from our group have been carried out on the use of halogens as a binding motif in cubanes [15], bicyclo[1.1.1]pentane [16], and nonplanar porphyrins [17]. Another reason to investigate the effect of meso halogenation of porphyrins is due to the potential of induced distortion of the macrocyclic core. Due to their relatively large size and high electronegativity, halogens induce a conformational distortion of the porphyrin core that is significant compared to those induced by other substitution groups. As recently illustrated in a review by Kielmann and Senge [18], the conformation of the porphyrin core can play a key role in the binding of small molecules or on its efficiency as an organocatalyst as demonstrated by Roucan et al. [19]. With the continuing interest in nonplanar porphyrins [20] and their relevance for the in vivo functioning of porphyrin cofactors [21], there is a significant importance of the knowledge of the conformation when designing supramolecular materials.
Studies on the effect of meso-halogenation have focused on the use of crystal data as a means of characterization [22], discriminating between enantiomers [23], or as a selfcontained structural discussion [24]. However, with all the advances made in the crystal engineering of planar porphyrins, investigation through exploration into the effect of meso-halogenation on the macrocycle architecture have, to date, not been carried out.
Herein, we present a comprehensive discussion of the interactions formed and 4 conformation for all deposited meso-halogenated porphyrins in the CCDC, accompanied by data obtained from our group. Hirshfeld fingerprints [25] were obtained to elucidate the intermolecular interactions and compare the respective contacts. This is complemented with the use of density functional theory (DFT) calculation of structures that have currently not been determined due to difficulties of obtained crystals of sufficient quality for X-ray determination.

Results and Discussion
We present herein a comparative analysis of the crystallographic structural characteristics of 13 mesox-halo-substituted porphyrins combined with data obtained from the CCDC crystal structure database [26] that show and quantify a general structural motif that is consistent among the majority of mesox-halo-substituted porphyrins. Hirshfeld surface analysis (HSA) displayed that H···H, X···C, and X···H (where X is a halogen atom) interactions vastly contribute to the formation of the crystal networks. Additionally, DFT calculations were conducted for further exploration of the ground state geometries and concurrently frontier molecular orbitals (FMOs) and sigma-holes have been displayed.
Additionally, we have included the substituted derivative of 2 with an acetylene moiety (2A) to investigate the differences observed between alternative substitution types.

5
The labelled ORTEP and packing diagrams for compounds 1 and 2A are available in SI (Figure S1-S4). The first feature which is of interest is the crystal packing of each of the 5-halosubstituted compounds which appear affected by both halogen type and metal insertion. In compound 1 the main motifs seen are the face-to-face stacking at 3.326(4) Å ( Figure 2A) and the tilted edge-on interaction (~64°) ( Figure 2B). The other motif seen is the inline interactions where layers of porphyrins are lined up with the bromine atoms pointing towards the phenyl rings in a ↑↓↑↓ repeating pattern ( Figure 2C).
However, in this structure, there is no apparent halogen bonding. By the addition of a nickel(II) metal center to compound 1, we obtain the structure of compound 2 [27]. In this structure a variety of changes in the overall porphyrin conformation are observed due to the metal center insertion. The first of these is the stacking between the porphyrin rings (at 3.581(3) Å), which now features the bromine atoms pointing in opposite directions with a ruffled conformation of the porphyrin macrocycle ( Figure 3A). Moreover, a similar motif of bromine atoms pointing towards the phenyl rings in a ↑↓↑↓ repeating pattern is visible in this structure and seems to be 7 a staple of this series ( Figure 3B). Secondly, the edge-on interaction in this structure has changed, where the pyrrole moiety is pointing towards the face of the porphyrin macrocycle as seen in Figure S5A. This is accompanied by a Br···H short contact [Br1···H12-C24; 3.291 (1) Å, 137.4 (7)°] which combines to form the packing seen in Figure S6. In compound 3 the packing of these structural archetypes is changed [22]. The stacking between macrocycle planes is similar to that of 2 (at 3.569(2) Å) ( Figure 4A).
Additionally, the edge-on interactions show the same tilted motif seen in compound 1.
However, this is combined with a new halogen directed close packing between the iodine atom and the edge of the porphyrin ring in a repeating step-wise pattern which is not seen in the other two structures ( Figure 4B). While this may be difficult to visualize in the crystal packing ( Figure S7), it is clear from the Hirshfeld surface analysis that there are marked decreases in the X···H contacts and an increase in the X···C (where X is a halogen atom) between compounds 1 and 3 ( Figure S8). The differences observed for bond lengths and angles incurred by increasing the atom size are minimal between Br (1) and I (3); in most cases it is less than 0.01 Å change (Table S1). Of note, in this case, is the marked decrease in the ∠CaCmCa of 2° seen in compound 3. Generally, all atom displacements (Δ24, ΔN, ΔCa, ΔCb, and ΔCm) [20] show a significant increase along with the pyrrole tilt angle moderately increasing when substituting a bromine atom for an iodine atom. This, however, does not change the core size to any large degree. To further investigate these subtle differences, we can look at their Normal-coordinate Structural Decomposition (NSD) profiles ( Figure S9) [28]. It can be observed that in the out-of-plane (OOP) distortion modes, the overall DOOP is almost tripled between compound 1 and 3 due to an increase in the saddle (B2u) conformation, while little change has occurred in the in-plane (IP) with a moderate increase in the B2g. While an increase in the size of the substituted halogen has a moderate effect, a much larger effect is observed due to metal insertion. This is seen as a general decrease in the bond lengths, bond angles, and core size, corresponding to a significant increase in atom displacement and pyrrole tilt angles. 9 This is essentially due to the ruffling caused by inserting a nickel(II) center [29][30][31] and is reflected in the NSD by a large increase in the contribution of the B1u OOP mode.
While the differences between halogen size and metal insertion are apparent, we were fortunate to obtain the structure of the acetylene substituted derivative of compound 2 (2A). In this structure, we can look at the changes between 2A and its bromo derivative 2. The first thing to note is how planar this structure is (see Table S1). Even with the inclusion of nickel(II) in compound 2A most of its bond lengths, bond angles, and core size are reduced, similar to compound 2, as seen in Table S1. However, the atom displacement is more akin to that of compound 3 showing little deviation within the macrocycle core. The combination of these features results in a packing like the one observed in compound 1 ( Figure S4) with the same stacking, edge-on interaction and layers of porphyrin with ↑↓↑↓ repeating pattern ( Figure S10). This is also reflected in the NSD where the largest contribution is seen in the B1u OOP mode, but it is not much more significant than compound 3. In the IP distortion modes, it has the lowest DIP contribution. This indicates that the effect a meso-substituted halogen has on the porphyrin macrocycle can be observed in the NSD with increasing halogen size evident in both the OOP and IP ( Figure S9). Additionally, the combination of a metal center and a halogen atom seems to have a greater impact than the sum of its individual effects in the OOP, while marginal differences are observed in the IP.

5-Halo-15-phenyl-substituted Porphyrins
Next, we are looking at the 5-halo-15-phenyl porphyrins with a varied selection of 10,20-substitution. We have obtained the crystal data for a selection of Cl, Br, and I porphyrins with either tolyl, hexyl, or phenyl substituents in the 10,20-position   Figure S21D). These features combine to make a complex packing system seen in Figure S12. The addition of the tolyl group breaks the highordered packing previously observed. The chlorine atom does not appear to have any substantial interactions present in the crystal structure.
The structure of compound 5 only differs from the structure of compound 1 by the addition of a phenyl moiety. In this structure, the same porphyrin overlap seen in Figure   2A is apparent ( Figure S22A) with a separation of 3.359(2) Å between the porphyrin layers. This is coupled with a short contact between the bromine atoms and the metahydrogen of the phenyl ring tethering porphyrin molecules to the one above it (Table   1). Considering the bond lengths, angles, and atom displacement there are only marginal differences in each case except for a notable increase in the atom displacement and pyrrole tilt angles (Table S2). This is represented by an increase in 11 OOP distortion mainly in the Eg(y) distortion mode and a second contribution to the Eg(y), while there are no changes to the IP modes ( Figure S23).
With the introduction of a hexyl group to the 10,20-position of the porphyrin ring, the complete packing arrangement is changed. Compounds 6 and 7 both show a preference for interacting in a head-to-head fashion with a Br···H interaction seen between the bromine atoms and the pyrrole unit for 6 ( Figure S24A) or the hexyl chain for 7 ( Figure S24B) (see Table 1 for distances and angles). However, the main feature of this type is the packing, where the porphyrin macrocycles are stacked with hexyl chains aggregating with each other (6, 3.270(5) Å, Figure S24C) (7, 3.316(4) Å, Figure   S24D). Looking at the bond lengths and angles (Table S2) The final structure in this series is the iodine and hexyl combination (compound 8). In this structure, the stacking is above with a separation of 3.255(5) Å ( Figure S25).
Interestingly, this structure features both arrangements previously seen with a close packing observed between both pyrrole ( Figure S26A) and hexyl ( Figure S26B) units depending on the residue in the asymmetric unit. Considering the bond lengths and angles (Table S2), there are almost no differences between compound 6 and 8 suggesting that little effect is caused by increasing the size of the halogen atom. This is also seen in the NSD where the overall profiles are similar to compound 6, in the IP with only a small difference observed in the OOP due to a shift from the Eg(x) to the Eg(y) closer aligned to compound 4.
To elucidate the intermolecular interactions, the Hirshfeld surface analyses were obtained ( Figure S27). These fingerprint plots showed that X···H (halogen···hydrogen) contacts appear in a relatively similar percentage for compounds 4-8 and X···C contacts are the most numerous contributors between the interacting atoms.
Regarding the substitution at positions 10 and 20, it is pointed out that the hexyl groups affect the pattern of C···H (decrease of the percentage) and H···H (increase of the percentage) contacts.
The labelled ORTEP and packing diagrams for compounds 9, 10, 11, and 13 are available in SI ( Figure S28-S36). The main feature of this series is the increase in the number of X···H interactions and the appearance of X···X (halogen···halogen) interactions which are outlined in Table S3. The structure of compound 9 shows three motifs driven by Br···H interactions ( Figure   S37) that when combined ( Figure S38) establish the packing pattern ( Figure S29). As with compound 1, the stacking between the porphyrin layers is organized with the bromine atoms overlapping with each other at a separation of 3.306(3) Å among the porphyrin macrocycles. In compound 9 we see a structure that is similar to both compounds 1 and 5 in basic architecture. This is reflected in the bond lengths, angles, and atom displacement (Table S4) where a similar distance is observed for both compounds 1 and 5. It is in the atom displacement that the effect of the di-bromination is apparent. The addition of a phenyl ring to the 15-position (compound 5) increases the disorder observed. However, when this is changed to a bromine atom, an alleviation of ring strain is observed resulting in a structure that is more planar than compound 1. Substituting the phenyl groups for a tolyl as in compound 10 results in a similar structure with bond lengths, etc. (Table S4) except for a marginal increase in the atom displacement and pyrrole tilt angles. While these changes are only minimal, 14 there is a variation of the packing compared to 9 with a more V-shaped pattern ( Figure   S31). This is directed by a combination of Br···H interaction between the bromine and the methyl moiety rather than aromatic hydrogens ( Figure S39A) and the tilted edgeon interaction ( Figure S39B). Comparing the NSD profiles of both samples their IP profiles are almost identical, but the extra distortion can be seen in the OOP with an increasing contribution of the Eg(x).
Compound 11 adopts a packing arrangement that is unique among the compounds studied in this section. As seen in Figure S41A, one central porphyrin is surrounded on four sides by four other porphyrin molecules. This is tethered through a selection of Br···H interactions which are outlined in Table S3. The second motif seen in this structure is a Br···H interaction which is reciprocated between two porphyrin molecules ( Figure S41B) and Br···Br contact on the opposite side ( Figure S42). The bond lengths etc. are typical of nickel(II) porphyrins, however, it appears that the distortion of compound 11 is much greater than the other nickel(II) porphyrins within this series.
The distortion of this structure is almost twice large as the second-largest distortion (compound 2) which is reflected in both the OOP and IP ( Figure S40) and can be seen in the larger increase of the atom displacements and pyrrole tilt angles (Table S4).
The structure of compound 12 is an interesting example of the effects that long alkyl chains have on the overall packing. This is seen as the preferred alignment of alkyl chain with each other, reminiscent of a lipid bilayer ( Figure S43) [23]. There are four motifs that contribute to the overall packing seen in Figure S44. The first two ( Figure   S43A and B) are directed through alkyl interactions with a head-to-head overlap ( Figure S43A) and the stacked system ( Figure S43B). The third motif is the closepacked side-on alignment which is due to the space occupied by the bromine atom, although there is no indication of potential halogen interactions. The final motif is a head-to-head Br···H contact between the porphyrin macrocycles ( Figure S44) which 15 tether the porphyrin together extending the network to be an alkyl···porphyrin···alkyl···porphyrin type system.
In the next three compounds 13, 13A, and 14 the main structure only differs by the steric demand due to one meso aryl unit (3,4,5-trimethoxyphenyl (13 and 13A), 2,4,6trimethoxyphenyl (14)) on one side [24]. Compound 13 is a recollection of the older sample 13A and is almost identical in structure. Both feature a parallel alignment of porphyrins tied together with the reciprocated Br···H contacts with the pyrrole hydrogens and a second contact between the bromine and the p-methoxy hydrogens ( Figure S45A, Figure S46A). Both structures also feature the hexyl chain overlapping with the face of the porphyrin ring ( Figure S45B, Figure S46B, Figure S47). Compound 14 forms a similar parallel alignment as the one seen in compounds 13 and 13A ( Figure   S48A) with the o-methoxy hydrogens interacting with the bromine atom. Additionally, there is the presence of weakly π-stacked dimers in the crystal with a hexyl chain on the same face as a neighboring aryl group ( Figure S48B). This results in a closer contact between the porphyrin layers compared to the packing of compounds 13 and 13A ( Figure S49). However, these deviations are in line with crystal packing and minor steric effects to be expected for this class of compounds.
The final compound in this series is 15. In this structure, the porphyrins rings are set up in an edge-on interaction with both sides of the porphyrin ring tethered through the bromine atoms and the aryl units ( Figure S50) [32]. On the side containing the axial THF molecule these interactions hold the pyrrole unit towards the face of the porphyrin ( Figure S50A). On the opposite side, the pyrrole units are held above the central metal atom through one Br···H contact ( Figure S50B). This forms a repeating pattern of faceto-edge interactions with only minimal interference from the axial ligand ( Figure S51A) and a hydrogen-bonded network between the methoxy moieties ( Figure S51B). Both features are expressed throughout the crystal packing ( Figure S52). 16 Hirshfeld surface analysis maps the corresponding intermolecular interactions with H···H contacts being the dominant ones with minor alterations in the percentage between this series of halogenated porphyrins ( Figure S53). Only compound 12 displays a higher percentage of H···H contacts together with a lower percentage of X···H contacts compared with the rest of the compounds. C···H contacts for compounds 9-11 are slightly higher than the respective ones of compounds 12-15, and X···C contacts do not display any significant difference amongst them. It is shown that the alkyl group, this time the hexadecyloxy group, can affect the pattern of C···H (decrease of the percentage) and H···H (increase of the percentage) contacts.

5,10-Di-halo-substituted Porphyrins
In this series, we are investigating the effects 5,10-di-halo-substitution that contain  Compounds 16-18 are a series of structures that only differ by the type of metal center in the porphyrin core [33,34]. In compound 16 the stacked porphyrin layers are orientated in a parallel arrangement with a 3.704(4) Å separation ( Figure S56A) whilst a lateral alignment where the bromine atoms are pointing towards the tolyl groups in a linear network is observed ( Figure S56B). The two other motifs seen are the bromine pyrrole interactions which is reciprocated in a head-to-head alignment ( Figure S56C) and the bromine tolyl interaction in a head-to-tail alignment ( Figure S56D), which combine to form the packing illustrated in Figure S57. By substituting the bromine atoms with a TMS-acetylene group the apparent lateral alignment of 16A is distorted due to the larger steric demand of the TMS moiety ( Figure S58A). Additionally, while this structure expresses the same head-to-tail overlap between stacked moieties (separation between layers at 3.573(3) Å), shows a greater degree of overlap ( Figure   S58B). In compound 17, the stacking has alternated to a head-to-tail overlap with 3.562(5) Å separation between the porphyrin layers ( Figure S59A). Moreover, there is a head-to-tail linear network ( Figure S59B) which is tied together with a Br···H contact with the aryl hydrogens. The combination of the vertical stacking and the lateral network forms the crystal packing ( Figure S60). Compound 18 exhibits the same lateral alignment seen in the previous two structures, with all axial solvents pointing in the same direction ( Figure S61A). The differences occur due to the presence of the axial methanol solvent in which the solvent hydrogen atoms interact with the bromine atom creating a staggering network ( Figure S61B). Two other stacking motifs are noted in this structure on either side of the porphyrin face. The first is the stacking between two molecules where axial solvents are sandwiched between the porphyrin layers at a separation of 4.432(4) Å ( Figure S62A). On the opposite side of the porphyrin, there is a weak stacking interaction at a separation of 3.215(3) Å ( Figure S62B). These features are expressed in the crystal packing in a repeating pattern ( Figure S63).  (5) The final compound in this series contains a 3,5-di-tert-butylphenyl in the 15,20position of the porphyrin ring (compound 19) [35]. This structure is a step up in steric bulk compared to compounds 16-18. With this addition, the inline alignment of porphyrins previously seen has changed to a step-wise pattern though a Br···H interaction with the four nearest neighbors ( Figure S64). The stacking seen in this structure is directed mainly to accommodate the large size of the aryl subunit creating a slightly offset stacking pattern with a separation of 3.4526(7) Å ( Figure S65). This creates a tightly packed structure ( Figure S66).
Overall, in this series one of the main features that is consistent is the network between the bromine atoms and the tolyl groups with only minor differences due to the insertion of a metal center and axial solvent molecules. This is seen in the Hirshfeld surface analysis, where only small variations in the percentage of contacts formed between compounds 16-18 with a marginal increase in the H···H and a decrease in C···H contacts in compound 19 due to the bulky tert-butyl groups ( Figure S67). With regards to bond lengths, angles, and atom displacement, there are only minor differences seen due to the inclusion of the metal center with compound 18 showing the lowest distortion with a small decrease in the atom displacement (Table S6). This is further compounded when moving to compound 19 with the large steric groups appearing to cause much more planar conformation of the porphyrin macrocycle. This is exemplified in the NSD profiles ( Figure S68

Other Halogeno-substituted Porphyrins
In the CCDC database, there are a few other notable examples which whilst they are interesting, they do not constitute a significant library to support a complete discussion (compounds 20-23, Figure 8) [36][37][38] Other examples do exist in the CCDC, such as strapped systems [39], but have been omitted due to the alternate functionality muting any effect the halogen would have on the porphyrin molecule. The bond lengths, angles, and atom displacements are outlined in Table S7. 20 Figure 8: Honorable mentions.
In the structure of compound 20, while containing a halogen, it is apparent that the fluorine atom is too small to overly impact the overall packing. This structure has a planar conformation similar to that of 2,3,7,8,12,13,17,18-octaethylporphyrin [40]. Due to the high disorder in the crystal structure (the fluorine atom is disordered over the four meso positions) an accurate accounting of the interaction profile is not possible.
However, there is the appearance of an F···H interaction between the ethyl groups and the fluorine atom which is projected throughout the crystal packing ( Figure S69). In compounds 21 and 22, the number of β-halogen atoms create two different packing patterns. The first is the head-to-head interactions directed through the chlorine atoms interacting with the tert-butyl hydrogens ( Figure S70A). With the addition of a second beta halogen, this motif drastically changes to become a face-to-edge interaction with the halogen atoms pointing towards the center of the porphyrin ring ( Figure S70B).
This second β-halogen creates a much more ordered packing pattern compared to 21 ( Figure S71). The final structure (23) is the only example of a porphyrin dimer with a di-halogeno-substitution. Interestingly, this structure despite the extended dual-core and tilt of the porphyrin rings behaves quite like a 5,15-di-halo-substituted porphyrin.
The bromine atoms are seen to interact with the tert-butyl and pyrrole hydrogen atoms in a head-to-tail arrangement ( Figure S72) which is propagated through the crystal packing ( Figure S73). Finally, the structure of 24 is included due to the presence of 2A and 16A ( Figure S74-S75). As a series of TMS-ethynyl structures, the features are generally similar to each other.

DFT Calculations and NSD Analysis
The limited availability of meso-halogenic porphyrin crystal structures in the CCDC makes it difficult to study a complete series. While we can develop certain trends based on the current data sets, the gaps present are a current limitation. To combat this, we decided to expand these series with ab-initio computational molecular modelling. We However, we were able to extract atom coordinates and NSD data which can be compared to the existing crystal structures [28,41].

Series 1
In series 1 ( Figure 9) the conformations of the mono-and di-substituted are only marginally different. The difference between the meso-free and fluorine derivatives is minimal. For the chloro to iodo derivatives, the di-substitution only exhibits a marginal decrease in the out-of-plane distortion relative to the mono-substitution, with the larger halogen inducing more planar conformation (see Figure S84, Table S11-S13). Upon the introduction of a metal center [nickel(II) in this case] the inverse is observed. The insertion of nickel introduces distortions of the porphyrin core similar to those that have been previously reported [29]. However, there is a secondary trend observed with the increase of halogen size showing a larger out-of-plane distortion, whilst the disubstitution mode having a larger impact in general. Interestingly, it appears that the effect of di-substitution is more pronounced than that of the mono-substitution with the immediate larger halogen. For example, di-Cl (1:10) has a larger distortion than the mono-substituted bromo-porphyrin (1D). In the in-plane distortion modes, the story is much simpler. The introduction of a metal center reduced the overall impact in the inplane distortion modes until this is alleviated by the effect of a larger halogen.
Increasing the halogen size shows a larger increase in the A1g contribution which  Finally, when comparing the calculated data (1D-3D) to that obtained via crystal structure analysis, there are small discrepancies (Table S14). In essence, the calculated data is a good approximation; however, the use of an idealized structure rather than an actual structure loses some of the accuracies that trends in NSD and other crystallographic explorations rely on. For example, most of the calculated data is only accurate to the first second decimal place while in some cases large differences are observed. This is most apparent when looking at the Δ24 of 3 and 3D where and difference of 5 times is observed between the simulated and crystal data. A clear trend is observed for the dihedral angle between the porphyrin and the phenyl rings. This dihedral angle is 69.2° for the unsubstituted diphenyl and increases as the halogen size and number of substituents increases, becoming almost perpendicular for the diiodo substituted (87.6°) (Table S8). Interestingly, this trend disappears when the metal is inserted, as a dihedral angle of approximately 81° is observed regardless of substitution. In conclusion, while the more desirable method is to use the actual crystal structures, the use of calculated data for structures that do not exists currently in the CCDC is a good approximation of the actual structure.

Series 2
In this series, we considered progressively increasing the number of halogens, taking 5-phenyl porphyrin as the base, and analyzed the effect on in-plane and out-of-plane distortions ( Figure 10). With the addition of one to three bromine atoms to the free meso-positions of the porphyrin, there is only a marginal shift in the out-of-plane distortion modes, with 5,10,15-substituted derivative having the largest (2:6) and 5,10substituted derivative having the smallest contributions (1:11) ( Figure S85, Table S15).
The largest of these contributions is seen in the B2u mode with a smaller but equal 25 contribution to the wave x and y modes. This is also represented in the bond lengths and angles with only minor deviations apparent (Table S15) (1D and 1:11), it appears that 26 these structures are more comparable to the 2:1-2:4. However, instead of the B2u being the largest mode, the contributions are seen in the Eg(x) and Eg(y) modes. In the in-plane mode, the largest contribution is seen in the A1g with a secondary contribution in the B2g. This indicates that while there is a minor effect of increasing the number of substituents, a larger impact is seen by the phenyl derivatives.
Therefore, the halogen substituents only marginally impact the porphyrin core with the in-plane demonstrating the largest shift.

Series 3
When considering the 5,10-di-halo-15,20-diphenyl substituted porphyrins ( Figure 11) there is a clear trend with regards to the influence of increasing halogen size on bond lengths, angles, and out-of-plane displacements (Table S16). The general trend is a marginal increase in the bond lengths and angles with the fluorine derivative being the lowest and iodine being the largest suggesting the influence of larger halogens has only a minor increasing effect. In the atom displacement, this trend is continued except for ΔN decreasing from fluorine to iodine derivatives. A clearer picture emerges when examining the NSD charts ( Figure S86).

Synthesis of 5-Chloro-10,20-bis(4-methylphenyl)-15-phenylporphyrin (4)
Pre-dried 5,15-bis(4-methylphenyl)-porphyrin, (100 mg, 0. The reaction entailed an attempt to prepare a meso-meso linked bisporophyrin via reaction of the starting material with PhLi followed by in situ oxidation to a radical anion and dimerization [51]. While formation of 5,10,15-trisubstituted porphyrins and 5,10,15,20-tetrasubstituted porphyrins was anticipated as side products, the detection of the title compound 4 was unexpected. The mechanism of the formation of 4 is not 30 easy to clarify, and presently, there is no indication of whether the reaction proceeds via a homolytic or heterolytic process. Notably, similar unexpected chlorination reactions have been described in the past [52,53]. While the metallated form of the product has been previously reported [52], this appears to be the first instance of the free base counterpart. One such study, using (5,15-bis(4methylphenyl)porphyrinato)zinc(II), alludes to nucleophilic substitution by Cl to form the chlorinated product, with the only possible source of the exogenous Cl atom during the study being DCM [52]. Another suggests that the chlorinated product may be formed from a Cl radical generated during the reaction, although it was not stated if the origin of the radical was DCM or DDQ [53]. Here, it was shown that the source of Cl to yield the meso-chlorinated porphyrin was DDQ, given the absence of DCM.
Investigations into why similar compounds as 4 were not frequently observed in previous research, and into the targeted synthesis of species 4 by DDQ are currently ongoing.

Crystallography
Crystals were grown using techniques following the protocol developed by Hope [54].
The crystal was mounted on a MiTeGen MicroMount and single-crystal X-ray diffraction data were collected on a Bruker APEX 2 DUO CCD, Rigaku CCD, or Bruker D8 Quest ECO diffractometer using graphite-monochromated Mo Kα (λ= 0.71073 Å) and Incoatec IμS CuKα (λ = 1.54178 Å) radiation at 100 (2), 112(2), and 123(2) K with an Oxford Cryosystems Cobra low-temperature device. Data were collected by using omega and phi scans and were corrected for Lorentz and polarization effects by using the APEX software suite [55][56][57][58]. Using Olex2, the structure was solved with the XS or XT structure solution program, using direct methods and refined against │F 2 │ with XL using least-squares minimization [59]. other atoms other H atoms. Details of data refinements can be found in Table S17-S20. All images were prepared by using Olex2 [58]. The iodine atom I1_2 was modelled over two positions using restraints SADI and constraint EADP in an 80:20% occupancy. The phenyl group (C151_2-C156_2) was modelled over two positions using restraints SADI and constraint EADP in a 50% occupancy. The phenyl group (C151_1-C156_1) was modelled over two positions using restraints SADI and constraint EADP in a 50% occupancy. The internal nitrogen atoms were modelled over two positions in a 50% occupancy. Compound 9: The internal nitrogen atoms were modelled over two positions in a 50% occupancy.

Previous Structures
Details on the refinement of NESHUO (2)  reported.

Hirshfeld Surface Analysis
The two-dimensional fingerprint plots and associated Hirshfeld surfaces [25,60] were calculated using CrystalExplorer [61]. The intermolecular contacts in crystal packing were visualized using dnorm surface. The di(outside) and de(outside) represent the distance to the Hirshfeld surface from nuclei. The proportional contribution of the contacts over the surface is visualized by the color gradient (blue to green) in the fingerprint plots.

Normal-coordinate Structural Decomposition (NSD) Analysis
The theoretical background and development of this method have been described by Shelnutt and co-workers [62,63]. NSD is a method that employs the decomposition of the conformation of the macrocycle by a basis set composed of its various normal modes of vibration, affording clear separation of the contributing distortions to the macrocycle conformation in a quantitative fashion. For calculations, we used our newly developed NSD generation program [28,41]. Tables S21-S23 contain the complete NSD out-put of compounds herein. Figure S87-S141 contains the file out-put of all compounds within this paper as obtained from the program.

DFT Calculations
The DFT calculations were performed using Gaussian 16 [64]. The wB97XD functional and a cc-pVDZ (cc-pVDZ-PP for iodine) basis set were used to optimize the ground state (S0) geometries using a tight convergence criterion. Frequency calculations were performed at the optimized geometries in order to confirm that the local minima were found. The molecular electrostatic potential (MEP) surfaces were generated by mapping the electrostatic potentials onto the 0.04 e/au 3 molecular electron density surfaces using the VMD software [65].

Supporting Information
Supporting Information File 1: