Interaction of Biologically Important Organic Molecules with the

Jan 16, 2015 - The interaction energies vary from 75 kJ mol–1 for glycine to 200 kJ ... The binding energy with Cr-MIL-101 is calculated to be −73...
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Interaction of Biologically Important Organic Molecules with the Unsaturated Copper Centers of the HKUST‑1 Metal−Organic Framework: an Ab-Initio Study Barbara Supronowicz, Andreas Mavrandonakis,* and Thomas Heine Jacobs University Bremen, School of Engineering and Science, Campus Ring 1, 28759 Bremen, Germany S Supporting Information *

ABSTRACT: Metal−organic frameworks (MOFs) provide new possibilities for their potential use in catalysis, gas storage/ separation, and drug delivery. In this work, a computational study is performed on the interaction of biologically important organic molecules such as caffeine, urea, niacin, and glycine with the undercoordinated copper centers of the HKUST-1 MOF. Density functional theory calculations are used to identify the adsorption sites of the organic molecules in HKUST-1 and to calculate their interaction energies. Two types of interactions are calculated: (i) strong binding via their nitrogen or oxygen atoms with the copper atoms of the paddlewheel and (ii) hydrogen bonds with the carboxylate groups of the MOF. Certain molecules such as caffeine and niacin can interact simultaneously with more than two paddlewheels, thus making the interactions even stronger. The interaction energies vary from 75 kJ mol−1 for glycine to 200 kJ mol−1 for caffeine. The confinement of the guest molecules in the cage windows of the framework can also create strong interactions. To take into account the effect of coordination with multiple paddlewheels, a very large model of the HKUST-1 needs to be used. The numbers of (i) copper sites interacting with the guest molecule and (ii) hydrogen bonds between the carboxylate groups of the MOF and the guests have a major impact on binding strength. This is important information when applying rational design to create new MOFs that should serve as drug carriers.

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INTRODUCTION In the past 20 years, porous coordination materials (PCMs), such as metal− and covalent−organic frameworks (MOFs and COFs, respectively), have attracted significant attention because of their possible applications in the fields of catalysis, gas storage, and sieving.1−14 Yaghi and co-workers15 synthesized MOFs for the first time in 1995, using the reticular chemistry approach. MOFs consist of secondary building units (SBUs), usually organic ligands and metal connectors, which are combined and extended into a framework. Properties of the resulting structure might be tuned according to the needs by the choice of proper organic ligands and metal connectors, for example, to narrow or expand the channels connecting the nanopores. Therefore, PCMs have been investigated in the fields of biomedicine,16,17 e.g., for drug delivery,17,18 and imaging.17−19 The most extensively studied molecule for drug delivery or adsorption in MOFs is ibuprofen.19−22 Horcajada et al.19 tested storage capacities of different MOFs with ibuprofen, caffeine, urea, and benzophenone. They achieved high urea loadings in MIL-100 and MIL-53 (69.2 and 63.5 wt %, respectively) and lower loadings for ibuprofen (33 and 22 wt %, respectively) and caffeine (24.2 and 23.1 wt %, respectively). A recent combined experimental and computational study showed the successful confinement of caffeine in several functionalized Zr-MOFs.23,24 Various experiments complemented by the density functional theory (DFT) calculations have investigated the most favorable © 2015 American Chemical Society

adsorption sites of caffeine inside of the framework. The authors have proven that the functional groups are not strong binding sites, and caffeine prefers to be adsorbed close to the organic linker. The polarity of the functional group plays a minor role in caffeine uptake, while strong competition with the water solvent is the cause of the poor drug loading. Only a few computational studies of the interaction of biologically important organic molecules with MOFs exist. Babarao et al.25 studied the energetics and dynamics of ibuprofen in two different MOFs. By means of DFT and molecular mechanics calculations, the most stable configurations of ibuprofen in Cr-MIL-101 and UMCM-1 have been found. The authors report much stronger binding for Cr-MIL101 than for UMCM-1. Cr-MIL-101 is a structure based on a Cr3O connector, which possesses undercoordinated chromium centers, while UMCM-1 consists of Zn4O connectors with fully coordinated metal centers. Ibuprofen forms a bond of 2.14 Å via the carboxylic group with the chromium atoms. The binding energy with Cr-MIL-101 is calculated to be −73 kJ mol−1, whereas with UMCM-1, which does not form strong bonds with ibuprofen, it is estimated to be −35 kJ mol−1.18 In two recent works, the interaction of the drug tamoxifen and the two amino acids glycine and tyrosine, with a Received: July 17, 2014 Revised: January 16, 2015 Published: January 16, 2015 3024

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The Journal of Physical Chemistry C functionalized IRMOF-14, has been studied.26,27 The organic linker is functionalized with a hydroxyl group, which acts as an anchor to the organic molecules. They are attached noncovalently via their amino groups to the MOF, with H-bonds formed with the hydroxyl group of the linker. The interaction energy with the functionalized linker is calculated to be approximately −40 to −65 kJ mol−1, which is larger for a typical hydrogen bond (approximately 20−30 kJ mol−1).13 The encapsulation of caffeine,16 busulfan,20 and ibuprofen22 in MIL-53(Fe) has been also studied by means of DFT. It was revealed that the presence of the OH groups on the surface of the framework governs the mechanism, allowing strong linking of the guest to the pore wall. According to the results, ibuprofen binds strongly with the oxygen of its carboxylic group to the previously mentioned OH group of the framework, while busulfan interacts with the oxygen atoms of its sulfonate functional groups. This leads to a higher binding energy of −69.6 kJ mol−1, compared to −57.4 kJ mol−1 for ibuprofen.22 Caffeine binds stronger than ibuprofen, with an interaction energy of −62.6 kJ mol−1. This is due to additional interactions with the framework rising from the more pronounced confinement.16 On the basis of the conclusions from the aforementioned works,17,20,22−24 we have decided to study the adsorption of biologically important molecules in MOFs with exposed metal sites, such as HKUST-1. We have chosen this MOF because of its extraordinary properties, such as a large pore size, few adsorption pockets, and the presence of undercoordinated metal sites. HKUST-1 consists of a bimetallic Cu−Cu connector linked to four benzene-1,3,5-tricarboxylate (BTC) species, resulting in a MOF with a stoichiometric formula of Cu3BTC2 and a tbo net topology. After the synthesis, solvent molecules [such as water and dimethylformamide (DMF)] are coordinated as axial ligands to the copper centers. When the sample is heated, the axial ligands can be removed creating an “activated” stable MOF, in which the original structure and topology are retained. After the activation process, the copper atoms remain unsaturated and act as primary adsorption sites. Their presence makes HKUST-1 an excellent candidate for gas storage,1,2,28−32 separation,33−40 and catalysis.41,42 To the best of our knowledge, there are no data available in the literature concerning the adsorption of biologically important molecules in the HKUST-1 MOF. However, there are several studies of the adducts of biologically important molecules on various dicopper paddlewheel compounds, such as dicopper formate [Cu 2(OOCH)4 ], dicopper acetate [Cu2(OOCCH3)4], and dicopper benzoate [Cu2(OOC-Ph)4]. In all these cases, the two copper atoms are bridged by four carboxylate groups, whereas each copper center has a square pyramidal geometry. Thus, these copper centers have the same chemical environment as in HKUST-1. In these studies, the axial position of the metal atoms is occupied by urea, caffeine, or nicotinamide molecules.43−48 These reports concentrate on the structural and magnetic properties of the paddlewheel and how the different molecules affect the magnetic exchange constants and the magnetic susceptibility. However, there is no other information available about the energetics or the vibrational characteristics of these compounds. To date, the most widely studied MOFs for the adsorption and delivery of drugs were MIL-101 and MIL-53(Cr,Fe). The encapsulation in these MOFs is achieved in two ways, by noncovalent or covalent binding.16,18,23,24 In the latter, covalent binding of the drug to a functional group can be achieved after postsynthetic

modification of the MOF. Binding is stronger, and the drug is released after the decomposition of the MOF. In the former, release of the drug molecule is faster. However, the release rate depends not only on the binding strength of the guest molecule but also on many other parameters, such as the pore size, flexibility of the framework, and the media (water or simulated serum fluid). The active sites are crucial to ensuring strong binding of the adsorbate; thus, we are mainly interested in the interactions of the guest molecules with the coordinatively unsaturated metal centers of HKUST-1. As guest molecules, we have chosen caffeine, niacin, urea, and glycine, which serve an important role in body. Urea metabolizes the nitrogen-containing compounds, and caffeine is of great interest to the cosmetics industry because of its lipolytic action and has a huge impact on the central nervous system by stimulating it. Niacin, also known as nicotinic acid, is one of the essential human nutrients. A deficiency of niacin in the body might lead to numerous diseases, such as nausea, skin and mouth lesions, anemia, headaches, etc. Glycine, one of the smallest amino acids, commonly found in proteins and acting as a neurotransmitter, is equally important. In this work, we investigate the energetics of the adsorption of these molecules in the HKUST-1 MOF. We consider not only the open metal sites but also the effect of confining the guests inside the pores of the framework. We are aware that the toxicity issues should be taken into account when designing drug carriers. Although copper is toxic, it exists in appreciable amounts in the body and is incorporated into a variety of proteins and metalloenzymes, and a daily dose of 2 mg is required.16 However, the scope of this work is not to suggest HKUST-1 as a potential drug carrier for biomedical applications, but to study the encapsulation of these biologically important molecules in a framework with open metal sites.

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COMPUTATIONAL DETAILS The structure of HKUST-1 has been simulated by taking into account two models of increasing size. As a first model, a dicopper benzenetricarboxylate (Cu2BTC4) cluster was considered, where the distant carboxylate groups were saturated with protons to maintain the charge neutrality (Figure 1). Full geometry optimizations have been performed on the adsorption of the guest molecules on this paddlewheel model by using DFT methods. In some cases, the guest molecules were interacting via hydrogen bonds with the protons of the distant carboxylate groups, causing a highly distorted structure, in which the organic linkers were significantly displaced with respect to their original position. This conformation would be quite improbable in the periodic framework. For that reason, we decided to disregard the smaller model and consider only the second model. The second model consists of 12 paddlewheels that are interlinked and form a large pore in HKUST-1. Because of the large size of this model (more than 400 atoms), optimizations were performed with a cheaper and faster DFT method, but the interactions were calculated more accurately by applying a hybrid scheme. These optimized models, together with the guest molecules and the smaller ones, used for the more accurate calculations, are presented in Figure 2. As a first step, the geometries of all structures were optimized with the STATPT module of Turbomole, until the Cartesian gradients were smaller than 10−4 hartree a0−1 and the energy change was smaller than 10−6 hartree. No symmetry constraints 3025

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where E(MOF(guest))dimer denotes a ghost basis calculation without electrons and nuclear charges for the guest at the geometry of the dimer and E(guest)dimer a normal calculation of the guest molecule in the geometry of the dimer. It can be further decomposed into two terms: I.E = ΔEint + δE(total), where the second term δE(total) = δE(MOF) + δE(guest) is the total deformation energy of the MOF and guest calculated at the PBE-D3/def-SV(P) level. ΔEint is calculated with a hybrid B3LYP-D3/def-TZVP:PBE-D3/def2-SVP scheme. The low-level calculations for the large model are performed with the PBE-D3/def2-SVP method. The high-level calculations are conducted with a smaller model with the B3LYP-D3/def-TZVP method. The smaller model is chosen in such way that it contains the guest molecule and its neighboring paddlewheels, which interact with it. In some cases, three paddlewheel units had to be considered in the high-level calculations, because the guest molecule was bound on all three of them. As high-level correction to the energy, we define the difference HLcorr = [E(B3LYP) − E(PBE)]small for the smaller model, whereas the PBE energy for the large model is considered as the low-level energy.

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Figure 1. Molecular models of the guest molecules (a) urea, (b) glycine, (c) niacin, (d) caffeine, and the Cu2BTC4 cluster used for the primary calculations (e, side view; f, top view). Colors: orange for copper, green for carbon, and red for oxygen.

RESULTS Adsorption on the Copper Sites. We have studied the energetic and thermodynamic properties of guest molecules adsorbed on the model systems of the HKUST-1 MOF. The binding energies and enthalpies of adsorption of all the systems considered in this work are listed in Table 1. All the models used for the calculations are presented in Figure 2. For the sake of comparison, the interactions of a water molecule with the metal site are calculated using the same procedure. This will show if water is a strong competitor against the organic molecules and can displace them from being adsorbed on the metal site. Furthermore, it is a good example for testing the accuracy of our computational approach against other methods. According to the hybrid scheme, the interaction energy of a water molecule with the paddlewheel unit is −57.2 kJ mol−1. This value is in reasonable agreement with the B3LYP-D3/ TZVP values of −60.9 kJ mol−1 for interaction with a dicopper benzenetricarboxylate molecular cluster53 and the DFT/CC value of −55.3 kJ mol−1 for the periodic structure.56 The calculations show that the strongest binding between the undercoordinated copper atoms and guest molecules is found for caffeine (approximately −220 kJ mol−1 for all investigated conformers). Such a strong interaction is explained by the fact that the guest binds to three copper sites of the MOF. Several initial configurations were taken into account for caffeine, e.g., coordination via only one N or O atom. In all cases, the molecule is taking such a conformation, that caffeine can coordinate with three neighboring metal sites via the N, Oα, and Oβ atoms simultaneously. In all cases, the final structures have almost the same energy and geometry. For that reason, only one conformation is reported in the tables. Strong binding is also observed for both conformers of niacin. In one case, the molecule interacts with two metal sites via the N and O atoms, whereas in the second case, it interacts through only an η1-O conformation. According to the results, bonding via two atoms is stronger than that with only one by ∼44 kJ mol−1. In both cases, the complex is further stabilized by the formation of a hydrogen bond between the niacin and a carboxylate group of the paddlewheel. Weaker binding is calculated for urea and glycine molecules. The interactions of urea (−98.6 kJ mol−1) are stronger in the

were applied. The optimizations were conducted using the PBE exchange-correlation functional49 in combination with the double-ξ “def-SV(P)” basis set.50 The optimized minimumenergy structures were verified as stationary points on the potential energy surface by performing harmonic vibrational frequency calculations. Because of the large size of the system, only the partial frequencies of the guest molecules were computed by numerical differentiation of the energies and gradients by a positive and negative displacement of 0.01 a0 in all three Cartesian directions. For the hybrid energy scheme, the hybrid B3LYP functional51,52 was used in combination with the all-electron TZVP50 basis set. This method has also been used in our previous work, where the interactions of small molecules with HKUST-1 were studied.53 In all DFT calculations, the energies were corrected for the weak London dispersion forces with a damped 1/r6 term proposed by the latest dispersion scheme of Grimme (denoted as D3).54 All calculations were performed with Turbomole.55 The thermodynamic properties were calculated on the basis of the partial frequencies upon the harmonic approximation. The adsorption enthalpies (ΔHads) are calculated from ΔHads = I.E + ΔZPE

where I.E values are the electronic interaction energies and ΔZPE = ZPE(MOF···guest) − ZPE(guest). The electronic interaction energies are calculated from a hybrid high-level/low-level (HL/LL) scheme. By taking into account the basis set superposition error (BSSE), we calculate the interaction as I.E = [E(MOF···guest) − E(MOF(guest))dimer − E(guest(MOF))dimer ] + [E(MOF)dimer + E(guest)dimer − E(MOF)opt − E(guest)opt] 3026

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Figure 2. Optimized geometries of organic molecules interacting with the open metal sites in HKUST-1: (a) glycine(N), (b) glycine(Oα), (c) glycine(Oβ), (d) niacin(N), (e) niacin(Oα), (f) urea(N), (g) urea(O), and (h) caffeine. The ball-and-stick models represent the clusters for high-level calculations. In panel c, some of the framework’s atoms have been omitted for the sake of clarity. Colors: orange for copper, turquoise for carbon, red for oxygen, white for hydrogen, and blue for nitrogen.

case of the η1-O conformer than in the case of η1-N by ∼7 kJ mol−1 (−89.0 kJ mol−1). In the first case, the dimer is further stabilized by an additional H-bond of the amino group of the urea with the carboxylate group of the paddlewheel. In the case of glycine, three possible binding modes have been identified: an η1-N and two oxygen conformers (η1-O and η1-O1). Despite the symmetric orientation of the oxygen atoms in the guest molecule, the relative difference in interaction energies for two oxygen modes is 13.6 kJ mol−1. This difference exists because a different type of oxygen atom is coordinated to the metal site (the carboxylic oxygen vs the carbonyl). The third conformation (binding via the N atom) is the strongest, and an interaction energy of −98.0 kJ mol−1 is calculated versus values of −84.3 and −74.6 kJ mol−1, respectively, for the other two. This is expected, on the basis of the investigation by Koukaras et al.,26 who has tested different orientations of

glycine in IRMOF-14. Their conclusion was that the strongest binding occurred with the functionalized linker of the framework. It has been shown that the strongest interactions occur for binding via the nitrogen atom. In the case of HKUST1, the guest interacts strongly with the undercoordinated Cu2+ center; thus, the binding is almost 3 times stronger than in case of the linker of IRMOF-14. The high-level (HL) corrections are always negative and contribute between 8 and 35 kJ mol−1 to the total interaction energy. The magnitude of the HL corrections depends on the mode of coordination of the guest molecule to the paddlewheel. For a bidentate coordination, the corrections are almost 2 times greater than those of monodentate binding. For the monodentate case, the average value for the HL corrections is ∼10 kJ mol−1, as listed in Table 1. It increases to 18 kJ mol−1 for the bidentate case of (η1-N:η1-O)-niacin and 3027

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Table 1. Interaction Energies from the Low-Level [ΔEint(low)] and High-Level (I.E) Methods, Corrections from the High-Level (HLcorr) Methods, and Deformation Energies [δE(total)] in kJ mol−1 binding modea urea

glycine

caffeine niacin

H2O

1

(η -N)-Cu (η1-O)-Cu LCW SCW (η1-N)-Cu (η1-Oα)-Cu (η1-Oβ)-Cu LCW SCW (η1-N:η1-O:η1-O)-Cu LCW (η1-N:η1-O)-Cu (η1-O)-Cu LCW (η1-O)-Cu LCW SCW

ΔEint(low)Bb

HLcorrSc

δE(total)d

I.Ee

ΔZPEf

D0g

−92.7 −119.2 −60.0 −50.3 −100.6 −86.6 −100.2 −61.4 −55.1 −221.3 −81.2 −168.2 −124.4 −103.7 −61.4 −22.4 −29.7

−9.1 −12.7 +1.3 −4.7 −12.2 −3.1 −7.9 −3.3 −11.6 −35.1 −9.4 −18.0 −13.7 −12.1 −0.8 −3.3 −3.1

+12.8 +33.2 +10.4 +4.1 +14.8 +16.0 +23.8 +12.7 +10.0 +41.8 +6.5 +30.0 +23.9 +17.9 +5.1 +0.9 +4.0

−89.0 −98.6 −48.3 −50.9 −98.0 −73.6 −84.3 −52.0 −56.6 −214.6 −84.1 −156.2 −114.2 −97.8 −57.2 −24.8 −28.7

+8.3 +6.4 +3.2 +3.3 +6.2 +4.2 +4.1 +3.8 +3.4 +10.5 +5.6 +7.7 +6.9 +4.6 +10.2 +8.5 +7.3

−89.0 −98.6 −45.0 −47.6 −91.8 −69.4 −80.2 −48.2 −53.2 −204.1 −62.6 −148.6 −107.3 −93.3 −47.0 −16.3 −21.4

LCW and SCW stand for large and small cage window, respectively. bΔEint(low)B is the low-level PBE-D3/def2-SVP energy for the large model. HLcorrS is the high-level correction, which is done for the small model. It is calculated as HLcorr = [E(B3LYP) − E(PBE)]small. dδE(total) is the total deformation energy of the MOF and guest molecule. eI.E is the total interaction energy from the hybrid scheme including the high-level corrections and the deformation energies. fΔZPE is the change in the zero-point energy upon adsorption. Only the frequencies of the guest are taken into account. It is calculated as ΔZPE = ZPE(guest@MOF) − ZPE(guest)gas. gD0 = I.E + ΔZPE. a c

reaches 35 kJ mol−1 for the tridentate coordination of caffeine. Thus, there is an average contribution of ∼10 kJ mol−1 for each binding mode. Unfortunately, we are not aware of any available data on the thermodynamic properties of the adsorbed organic molecules on HKUST-1. Nevertheless, obtained results let us conclude that the adsorption of biologically important organic molecules on the copper centers of HKUST-1 is significantly stronger than that of other small gases and especially that for water.53 The results are listed in Table 1. By using the same computational scheme, the adsorption enthalpy of water is calculated to be approximately −49.4 kJ mol−1, which is smaller than for any organic molecule. This value is in very good agreement with the DFT/CC calculated enthalpy of −49.0 kJ mol−1 and the experimental enthalpy of −50.7 kJ mol−1.56,57 This suggests that water is a weaker competitor. Thus, HKUST-1 is able to bind the organic molecules even in the presence of water, which is not the case with other small molecules as presented in our previous work.53 The Cu−Cu distance in the paddlewheel is always calculated to be ∼10 pm shorter than the available experimental data, either on the empty or on the occupied paddlewheel. This slight underestimation of the Cu−Cu distance arises from the PBE functional. However, the distances for the host−guest interactions are in good correlation with the available experimental data for caffeine, urea, and niacin (Table 2). For example, upon the adsorption of caffeine, the deviation of the Cu from the plane defined by four carboxylate oxygen atoms is 0.2 Å,43 whereas we have obtained a value of 0.24 Å. In the case of urea, the distances between the copper and oxygen differ only slightly from the experimental data. Additionally, according to ref 44, urea prefers to bind to copper with its oxygen atom rather than its nitrogen, which supports our results from Tables 1 and 2 (stronger interaction energies for the O isomer than for the N isomer).

Table 2. Calculated and Experimental Cu−Guest and Cu− Cu Distancesa Cu−X (pm) empty MOF (η1-N)-urea (η1-O)-urea (η1-N)-glycine (η1-Oα)-glycine (η1-Oβ)-glycine (η1-N:η1-Oα:η1-Oβ)-caffeine (η1-N:η1-O)-niacin (η1-O)-niacin a

222 (21945) 216 (211,44 213 and 21245) 217 216 232 232 (*22346 and 22343)/222/226 221/218 223 (22048)

Cu−Cu (pm) 246 (25860) 251 (26445) 256 (266,44 262 and 26645) 252 253 252 254 (*26546 and 26943) 254 253 (26148)

Values in parentheses correspond to those of experimental structures.

The calculated results for niacin are also in good agreement with the experimental values reported by other groups.23 The main distance between Cu and oxygen atom of the guest differs by only 1 pm, while the Cu−Cu bond is also 8 pm shorter in comparison with that given in ref 48. Like the other authors,48 we have also observed a hydrogen bond between the oxygen of the framework and the hydrogen of niacin (η-O binding mode). In all cases, the Cu−Cu distances in the paddlewheel are elongated by ∼7 pm upon binding with respect to those of the uncoordinated case. The same trend is also observed for the experimental crystal structures. Upon adsorption, significant changes are occurring in the geometries of both the framework and the guest molecule. The deformation energies are varying between 13 and 42 kJ mol−1 for the organic molecules and are estimated to be only 5 kJ mol−1 for the water case. For the organic molecules, most of the corresponding values are in the range of 6 and 8 kJ mol−1. The only exceptions are those of (η1Oα)- and (η1-Oβ)-glycine, which have values of 2 and 12 kJ mol−1, respectively. All values are summarized in Table 1 and presented more analytically in Table S1 of the Supporting 3028

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Figure 3. Optimized geometries of organic molecules interacting with LCW and SCW sites in HKUST-1: (a) glycine, LCW; (b) glycine, SCW; (c) niacin, LCW; (d) urea, SCW; (e) urea, LCW; and (f) caffeine, LCW.

the copper site. Confinement of the caffeine in the LCW creates strong interactions with the framework atoms, which are depicted by the value of approximately −84 kJ mol−1 for the interaction energies. The caffeine interacts through weak London forces with the framework atoms. The deformations caused by the confinement are quite small and amount to ∼4 and 3 kJ mol−1 for the framework and the guest, respectively. Similar behavior is observed for niacin, which can be also adsorbed only in the LCW, with an interaction energy of −98 kJ mol−1. The enhanced adsorption energy with respect to the caffeine can be explained by the formation of a hydrogen bond between its proton and the oxygen atom from the carboxylate group of the framework. The deformation energy is larger in this case (+17.9 kJ mol−1) and can be mainly attributed to the framework (+14.6 kJ mol−1). For urea, several conformations were identified. However, only the most stable ones are reported. Because of the smaller size, urea can be adsorbed in both cage windows, with almost equally strong binding energies. For LCW, a binding energy of −48.3 kJ mol−1 is calculated, and a value of −50.9 kJ mol−1 for the SCW. In both cases, urea forms four hydrogen bonds with the carboxylate oxygen atoms. In the LCW case, the deformation energies are larger (+10 kJ mol−1), whereas the value is only 4 kJ mol−1 for the SCW, thus destabilizing more the complex; that is why the SCW is the stronger adsorption point. However, the copper site is the strongest interaction site with almost twice the binding strength. Finally, similar behavior was calculated for glycine. Adsorption in the SCW (−56.6 kJ mol−1) is stronger than in the LCW (−52.0 kJ mol−1). In both cases, two hydrogen bonds are formed. In the SCW, glycine interacts via the two protons of the -NH2 group, whereas via one proton from the -COOH and one from the -NH2 group in the LCW. Comparison of the Adsorption in Metal Sites and Pores. In all cases, we found that interactions with the metal sites are the strongest. When the guest molecules are adsorbed in the cavities, they can form multiple strong hydrogen bonds with the carboxylate oxygen atoms of the framework. However,

Information. The framework undergoes a deformation larger than that of organic molecules, except for (η1-N)-urea and (η1N)- and (η1-Oβ)-glycine, which show deformation energies comparable to that of the MOF. The largest deformation energy of ∼46 kJ mol−1 for the MOF is calculated for the case of caffeine. This is expected, because caffeine is coordinated via three points. Three paddlewheel units have to undergo significant deformations, so that they can approach the nitrogen and oxygen atoms of the caffeine and form a bond. Similarly, a high deformation energy of 22 kJ mol−1 is calculated for (η1N:η1-O)-niacin. An unexpectedly large deformation of 25 kJ mol−1 for the framework is calculated for the (η1-O)-urea complex. In this case, the carboxylate groups are significantly distorted with respect to the empty structure. This is occurring because of the formation of two H-bonds between the amino groups of the urea and the carboxylate groups of the framework. To maximize the interactions of these hydrogen bonds, the carboxylate groups have to move quite a distance from their equilibrium position. Adsorption in the Pores. In this section, we discuss the adsorption of the guest molecules in the pores of HKUST-1. Following the notation of Grajciar et al., two cage windows of different sizes are present in HKUST-1.58 The smaller one has a triangular shape and is created by three paddlewheel units interconnected by three linkers. The larger one has an almost rectangular shape and is created by four paddlewheel units interconnected by four linkers. For each guest molecule, adsorption in small cage windows (SCW) and large cage windows (LCW) was considered. Several initial configurations of the guest molecule in the SCW and LCW were taken into account, and the geometry of the structure was optimized. The interaction energies were calculated as described in the previous sections, and the results are also summarized in Table 1. The geometries are presented in Figure 3. Caffeine can be adsorbed only in the LCW. Because of the large molecular size, adsorption in the SCW is not possible, and after optimization, it moves toward the pore and is adsorbed on 3029

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The Journal of Physical Chemistry C

Interesting effects are expected to appear at higher loadings because of guest−guest interactions, when all metal sites are occupied. For caffeine, urea, and glycine, the dimerization energies are stronger than the adsorption at LCW and SCW. Thus, these molecules are expected to create dimers and/or trimers instead of being adsorbed in the pores. The geometry of the paddlewheel changes upon adsorption. It is strongly dependent on the size, orientation, and number of the guests in the framework. A significant elongation of ∼10 pm for the Cu−Cu bond of the cluster has been calculated upon binding with the organic molecules. This result agrees with the available experimental data for various dicopper padlewheel compounds. It was necessary to simulate the structure of HKUST-1 by using a large molecular cluster. The reason is that some of the molecules can be coordinated simultaneously to two or three different neighboring paddlewheel units. Small cluster calculations are unsuitable and lead to incorrect conclusions about the adsorption properties of these species. All the values have been compared against water because unless the adsorption is performed in a dry environment, H2O will always compete for the open adsorption site. Our results show that any of the considered molecules would be adsorbed stronger. HKUST-1 is still unstable toward water, which limits its application in medical approaches, as toxic copper would be released into the body. However, this study is meant to guide the rational design of new materials that contain features present in HKUST-1 and may be used for the delivery of biologically important molecules.

in all cases, the interactions with the copper sites are significantly stronger. This was also reported in a recent work, where the authors screened various MOFs as potential drug carriers using Monte Carlo simulations.59 At zero loadings, they calculated higher values for the host−guest potential energies for MOFs with unsaturated metal sites than with fully coordinated metal sites. They attributed this difference to the interaction of the drug with the open metal sites, because at higher loadings the potential energies were decreasing. For some cases, they reported that at higher loadings the guest− guest interactions were becoming important and contributed significantly to the total potential energy. We also took into account the guest−guest interaction energies. On the basis of the work of Bernini et al., we compared the host−guest interaction energies versus the guest−guest interaction energies.59 For that reason, we optimized the geometries of the dimers and calculated the dimerization energies of the adsorbates. The results are listed in Table 3. For niacin, urea, and glycine, the dimers are formed via Table 3. Guest−Guest Interaction Energies (kJ mol−1) at the Optimized Geometry of the Dimer B3LYP-D3/TZVP

I.E

ΔZPE

D0

urea glycine caffeine niacin

−63.8 −79.8 −74.4 −77.1

+5.3 +2.9 +8.1 +4.3

−58.5 −76.9 −66.2 −72.8

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hydrogen bonds. Their corresponding formation energies are −72.8, −58.6, and −76.9 kJ mol−1, respectively. The caffeine dimer has a formation energy of −66.2 kJ mol−1 and is formed through π−π stacking of the rings. If we compare the dimerization values with the adsorption energies in HKUST1, we conclude that the metal site attraction is much stronger than the dimerization energy. However, guest−guest interactions may play an important role at higher loadings, when all metal sites are occupied. These interactions become competitive with respect to the adsorption energies at the LCW and SCW sites. Thus, it is expected that the guest molecules may start to interact with each other, instead of interacting with the LCW or SCW sites. The only exception is niacin, which has a lower dimerization energy (−72.8 kJ mol−1) versus the value of −93.3 kJ mol−1 for the LCW site.

ASSOCIATED CONTENT

S Supporting Information *

Cartesian coordinates of all structures and a table with the deformation energies. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge financial support from the Deutsche Forschungsgemeinschaft (DFG) through the Priority Programme SPP 1362 (Project MA 532/1-1). This work was performed using the computational resources of the CLAMV (Computational Laboratories for Analysis, Modeling and Visualization) at Jacobs University Bremen.

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CONCLUSIONS The adsorption of biologically important organic molecules in the HKUST-1 metal−organic framework has been investigated. To the best of our knowledge, this is the first study concerning the interaction of biologically important molecules with the HKUST-1 MOF. All the guest molecules bind strongly to the metal connector of the framework. The highest affinity is calculated for caffeine. The number of the copper sites interacting with the guest molecule has a major impact on the strength of the binding. This is important information when applying rational design to create new MOFs that should serve as drug carriers. Confinement of the guests in the pores can also create strong interactions, but not as strong compared with the copper sites. The guest molecules can interact via (i) hydrogen bonding with the carboxylate oxygens of the frameworks and (ii) weak London dispersions.

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