1,1,2,2-Tetracyanocyclopropane (TCCP) as supramolecular synthon †

The 1,1,2,2-tetracyanocyclopropane (TCCP) unit presents a synthetically accessible and versatile synthon that can interact with lone-pair or p -electrons by ‘non-covalent carbon bonding’. Complexes of TCCP with common small molecules, anions, aromatics like fullerenes, amino acids and nucleobases were computed at the DFT BP86-D3/def2-TZVP level of theory. Binding energies vary between about (cid:2) 10 kcal mol (cid:2) 1 for neutral guests and (cid:2) 15 to (cid:2) 50 kcal mol (cid:2) 1 for anionic species. This is comparable to strong and very strong hydrogen bonding respectively. Thus, in addition to synthons that contain polarized hydrogen or halogen atoms, TCCP presents a new supramolecular synthon that awaits experimental exploitation.

We have recently highlighted that sp 3 hybridized carbonthe most abundant tetrel atom in living matter -can be a supramolecular synthon. 47,48More specifically, the 1,1,2,2tetracyanocyclopropane (TCCP) motif (Scheme 1) was identified as an electron poor bowl, apt to accommodate an electron rich guest. 47Two convenient (high yielding) synthetic routes towards this motif are shown in Scheme 1: reaction of a primary or secondary alkyl halide with tetracyanoethylene (top); [57][58][59][60] and reaction of an aldehyde or ketone with malonitrile (bottom). 61,62In both instances, numerous variations of the R-bearing moieties are readily available and provide a convenient way to obtain a practically infinite amount of TCCP derivatives.Thus, TCCP provides a rather unique case of a synthetically versatile and accessible supramolecular synthon that awaits utilization by the molecular scientists.
Anticipating the experimental exploitation of TCCP, we here report on a comprehensive theoretical investigation of the binding interactions of a model for TCCP derivatives (where R 1 = R 2 = H) with three classes of compounds; commonly encountered small (neutral) molecules, common anions, and several aromatic systems including Nature's aromatic building blocks.

Results
For our enquiries we conducted computations based on density functional theory (DFT) at the BP86-D3/def2-TZVP level of theory and Table 1 summarized the results of the interaction of TCCP with common small molecules.For several of these molecule pairs, ab initio calculations at the MP2/def2-TZVP level of theory were also conducted (denoted 'a' in Table 1) to validate our use of the more economical DFT approach.The comparative results are given in the ESI † (Table S1) and are in excellent agreement: computed distances differ less than 3% and computed energies typically less than 10%.In all cases, the minimized complex was subjected to an 'atoms in molecules' (AIM) analysis in order to identify atoms engaging in bonding contacts. 64Graphical renderings of these analyses are depicted in Fig. S1 (ESI †), and Fig. 1 shows representative examples for some complexes with small neutral molecules.The complexation energy with the control guest methane (À2.3 kcal mol À1 ) is very small and methane actually is not located in the electron poor binding pocket of TCCP (see Fig. S1, ESI †).All other guests do engage in tetrel bonding with the C 2 (CN) 4 pocket, although in several structures additional hydrogen bonding with TCCP's N-atom(s) is also observed (i.e. in 4-6, 8, 10, 11, 20).These additional forces might explain the increased stability of these complexes over other, very similar ones.For example, the [H 2 OÁ Á ÁTCCP] pair 3 has an energy of À8.45 kcal mol À1 , solely due to OÁ Á ÁC tetrel bonding interactions, while the additional hydrogen bonds with dimethyl ether (4), 1,4dioxane (5) and THF (6) result in energies of about À11 kcal mol À1 .The energies of other small molecules with O-donors (7-16) are very similar, between about À7 and À10 kcal mol À1 .The strongest of these that do not have additional H-bonding according to AIM are trimethylphosphaneoxide 14 (À14.0kcal mol À1 ) and dimethylsulfoxide 16 (À12.2kcal mol À1 ).This is in line with the increased polarization of O in these molecules.
Other small molecules considered where an atom other than oxygen functions as electron donor (17-28) gave very similar energies, ranging between about À5 to about À10 kcal mol À1 .Carbon monoxide (17) and dinitrogen (18) displayed the lowest predicted energies at about À3 kcal mol À1 .
All anionic guests appears to sit comfortably within the electron poor bowl shape of TCCP, and are held in place solely  S1. b Also XHÁ Á ÁNC(TCCP) hydrogen bonding present according to AIM analysis.c Alternate orientation also considered (respectively marked 2 0 /17 0 /18 0 /28 0 in Fig. S1) but found to be less stable.d Another geometry where pyridine interacts with its p-cloud is less stable at À7.08 kcal mol À1 (see also complex 54 in Table 3).
Fig. 1 Molecular geometries of representative complexes of TCCP with small molecules, as computed at the BP86-D3/def2-TZVP level of theory (see also Table 1).The small red dots denote the bond-critical points according to an AIM analysis.
In general the interaction energies reported in Tables 1 and  2 are in good agreement with the MEP values of the guest molecules on their negative regions.For instance in the neutral O/N Lewis bases the MEP values vary from À58 kcal mol À1 [for (CH 3 ) 3 PO] to À12 kcal mol À1 (for N 2 ).Moreover, for the monoanionic guests, the MEP values vary from À216 kcal mol À1 (F À ) to À125 kcal mol À1 (PF 6 À ), in line with the interaction energies observed for their corresponding complexes.The SO 3 2À dianionic guest exhibits the most negative MEP value (À247 kcal mol À1 ) and the largest interaction energy (see Table 2).
As it appears from the data collected in Table 3, small isolated p-systems like ethene (50) and ethyne (51) bind to TCCP with about À5 kcal mol À1 .Small conjugated systems such as benzene (53) bind even stronger (about À7 kcal mol À1 ), while larger condensed hydrocarbons (55-60) such as pyrene (58) bind stronger still (about À10 kcal mol À1 ).As is apparent from the AIM analyses shown in Fig. 3, all these complexes are held together mainly by tetrel bonding interactions (in some cases perhaps stabilized by weak CNÁ Á ÁHC polar contacts).
It is interesting to note that the binding energy peaks at coronene (60; À12.6 kcal mol À1 ), which can be seen as a model for graphene.Likewise, the binding energies calculated with several fullerenes (61-64) are substantial and strongest for a model of carbon nanotube (12,0) at À12.6 kcal mol À1 (64).
Also noteworthy is the positioning of TCCP over pyrene in 58 and triphenylene in 59; apparently TCCP prefers the periphery over the center.It is known what Li + also preferentially binds to a peripheral ring in large condensed hydrocarbons. 65However, in 60 the TCCP sits perfectly above the center of the coronene.
Encouraged by the energies computed with small molecules and aromatic systems, we expected that Nature's aromatic building blocks could bind to TCCP as well.The computational verifications of this expectation are listed in Table 3 as complexes 65-73 and Fig. 4 shows the molecular structure and AIM analysis of several representative examples.Models of tyrosine 65 (À8.1 kcal mol À1 ) and tryptophan 66 (À11.7 kcal mol À1 ) interact much like condensed hydrocarbons, binding to TCCP with their p-electrons.Histidine 67 (À11.6 kcal mol À1 ) seems to prefer binding to TCCP with its N-atom.When protonated, histidine moves away from TCCP's electron poor binding pocket and instead establishes a strong hydrogen bond with one of the N-atoms in TCCP.The binding energies computed with the nucleobases (69-73) are very similar at Fig. 2 Molecular geometries of representative complexes of TCCP with anions, as computed at the BP86-D3/def2-TZVP level of theory (see also Table 2).The small red dots denote the bond-critical points according to an AIM analysis.about À11 kcal mol À1 .Adenine (69) and guanine (70) bind with their p-surfaces, while the thymine (71), cytosine (72) and uracil (73) interact with their lone-pair electrons on O and/or N and additional hydrogen bonding.
Next, we wondered how a host molecule with several appropriately-spaced TCCP units would interact with some size-complementary electron rich guests.To this end we conjured one bipodal and two tripodal claw-like hosts (Fig. S2, ESI †) in which the linking unit assures an appropriate space in between TCCP-moieties and also allows for the correct angles so that the C 2 (CN) 4 'binding pockets' can face each other.We computed interacting energies with a selection of guests (see Table 4).The molecular geometries of selected complexes are shown in Fig. 5 (the whole series is shown in Fig. S3, ESI †).AIM analyses were also performed and revealed tetrel bonding in all cases (not shown due to congested graphics).
The bipodal host interacts with some neutral and 'flat' molecules with about À5 to À10 kcal mol À1 (74-77); while the interaction of the spherical halide anions is much larger a Another geometry where pyridine interacts with its N-atom is more stable at À9.5 kcal mol À1 (see also complex 22 Table 1).b No interaction with the p-system.
Fig. 3 Molecular geometries of representative complexes of TCCP with p-systems, as computed at the BP86-D3/def2-TZVP level of theory (see also Table 3).The small red dots denote the bond-critical points according to an AIM analysis.
Fig. 4 Molecular geometries of complexes of TCCP with some of Nature's aromatic building blocks, as computed at the BP86-D3/def2-TZVP level of theory (see also Table 3).The small red dots denote the bond-critical points according to an AIM analysis.(84, 87) with interacting energies of about À20 to À40 kcal mol À1 .These energies are generally larger compared to the analogous interaction with a single TCCP unit (Tables 2 and 3).For example, 78 (À67.1 kcal mol À1 ) is about 30% more stable than 44 (À52.08 kcal mol À1 ) and 82 (À27.5 kcal mol À1 ) is about 60% more stable than 48 (À17.17kcal mol À1 ).That the stabilization is not strictly additive is likely a result of some repulsive interactions in the complex (e.g.CNÁ Á ÁNC), some strain on the conformation of the host (e.g. the Ar-CRC-CH 2 units in 82 and 84 are not perfectly linear), and/or the decreased electronegativity of the guest upon binding to one TCCP moiety.

Discussion and conclusions
From the above results it is clear that TCCP derivatives can accommodate a plethora of guest molecules that bear lone-pair electrons, p-electrons and/or a negative charge.The main mode of interaction with these electron rich entities is tetrel bonding with TCCP's electron deficient C 2 (CN) 4 bowl.Hydrogen bonding with the cyano N-atoms may further stabilize the complex (e.g.complex 6 with THF).
The binding energies of about À10 kcal mol À1 observed with various neutral guest molecules are comparable in strength to strong hydrogen bonding involving charge-neutral H-bonding pairs. 66The values of about À15 to À30 kcal mol À1 -typically observed with various anions -is truly remarkable because they are comparable in strength to very strong (ionic) hydrogen bonding. 66The exceptionally large enthalpies computed for H À (À43.4 kcal mol À1 ) HO À (À57.7 kcal mol À1 ) and F À (À52.1 kcal mol À1 ) even far exceed the common benchmark for strong hydrogen bonding (about À35 kcal mol À1 ). 66he large energies of formation computed between TCCP and (models of) fullerenes (about À10 kcal mol À1 ) was somewhat expected, as TCCP's bowl-like shape and electron positive core are complementary to the concave shape and electron rich surface of fullerenes.8][69][70] Other charge-neutral supramolecular approaches for binding fullerenes indeed seem far less apt.For example, typical binding energies of hydrogen-p and halogen-p interactions are estimated at about 1-5 kcal mol À1 , 71,72 while not being shape-complementary to fullerenes at all.
Perhaps the most important result is the difference in geometric preferences of TCCP binding to (models of) amino acids and nucleobases.This implies that TCCP derivatives might selectively nest themselves in proteins and DNA/RNAtype molecules.In this context it is worth mentioning that TCCP derivatives are expected to be poorly hydrated in aqueous solution (no strong H-bond donors) and thus also interact with biomolecules by virtue of the hydrophobic effect.The potential of TCCP derivatives to bind strongly and selectively to biomolecules implies that TCCP might be engineered to influence the functioning of biomachineries, which in turn might have pharmacological implications.Additionally, the bipodal and tripodal TCCP hosts illustrate that strategically placed TCCP-units may greatly enhance the affinity for a guest molecule, just like multiple H-bond donors within a protein can result in high affinity binding to a ligand.
In summary we highlighted that TCCP is an accessible supramolecular synthon that acts as an 'electron sponge', mainly by virtue of tetrel bonding interactions.Its unique bowl-like shape, electron deficient core, and (presumed) hydrophobic character make TCCP-derivatives a promising new addition to the (bio)chemists toolbox (e.g. the PDB is void of TCCP-like ligands).As a result, following this theoretical exploration we anticipate that experimental exploitation of this unit will soon unveil its functional potential.

Table 1 Interaction
energies (DE), minimum contact distances (D) and densities of bond critical points (r) estimated at the DFT BP86-D3/ def2-TZVP level of theory of complexes involving TCCP and several small molecules Complex Guest DE (kcal mol À1 ) D (Å) rÁ100 (a.u.)Control 1 CH 4 a À2.3 3.167 a 0.470 O-donor atom(s) 2 NC(O)H b À15.1a Complex also computed at the MP2/def2-TZVP level of theory, as detailed in Table

Table 2 Interaction
energies (D E), minimum contact distances (D) and densities of bond critical points (r) estimated at the DFT BP86-D3/def2-TZVP level of theory of complexes involving TCCP and several anions Complex Guest DE (kcal mol À1 ) D (Å) rÁ100 (a.u.) Anions with O-donor atoms and hydride

Table 3
Interaction energies (D E), minimum contact distances (D) and densities of bond critical points (r) estimated at the DFT BP86-D3/def2-TZVP level of theory of complexes involving TCCP and several p-systems