A Kinetic and Computational Study With Neutral and Cationic

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Cucurbituril Mediated Catalytic Hydrolysis: A Kinetic and Computational Study With Neutral and Cationic Dioxolanes in CB7 Leandro Scorsin, Juliano A Roehrs, Roberta R. Campedelli, Giovanni F. Caramori, Alexandre Osmar Ortolan, Renato Luis Tame Parreira, Haidi D. Fiedler, Angel Acuña, Luis García-Río, and Faruk Nome ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03605 • Publication Date (Web): 15 Nov 2018 Downloaded from http://pubs.acs.org on November 22, 2018

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ACS Catalysis

Cucurbituril Mediated Catalytic Hydrolysis: A Kinetic and Computational Study With Neutral and Cationic Dioxolanes in CB7 Leandro Scorsina, Juliano A. Roehrsb, Roberta R. Campedellia, Giovanni F. Caramoria, Alexandre O. Ortolana, Renato L. T. Parreirac, Haidi D. Fiedlera, Angel Acuñad, Luis GarcíaRíod* and Faruk Nomea* aDepartamento

de Química, Universidade Federal de Santa Catarina, Florianópolis-SC, 88040-

900, Brazil. bInstituto

Federal de Educação Ciência e Tecnologia Sul-rio-grandense - IFSul, Pelotas-RS,

96015-360, Brazil. cNúcleo

de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de Franca, Franca-SP,

14404-600, Brazil. dCentro

Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and

Departamento de Química Física, Universidade de Santiago, 15782 Santiago, Spain. ABSTRACT Cucurbit[7]uril, CB7, catalyzes the acid hydrolysis of alkoxyphenyldioxolanes bearing both neutral and cationic alkoxy groups. The magnitude of the catalytic effect depends on the dioxolane structure as reflected by both the CB7 binding constants and the catalyzed rate constants. However there is not a clear relationship in such a way that increasing the binding affinity (cationic dioxolanes or large alkoxy groups) does not enhance the catalytic effect. The A-1 mechanism for dioxolane hydrolysis involves the protonation and formation of a carbocation by protonated dioxolane ring opening. Supramolecular catalysis takes place through the formation of a ternary complex dioxolane@CB7@H3O+ where the hydronium ion is stabilized by hydrogen bonding with the carbonyl groups of the CB7 portal. The ternary complex evolves to a binary one by protonation of dioxolane and release of a water molecule. It is important to note that these structures are only stable in the presence of CB7 and not in bulk water. Carbocation is formed by opening the protonated dioxolane group in the rate determining step. The distance between the carbonyl portal of CB7 and the dioxolane group in the ternary and binary complexes (protonated and carbocation) increases with the alkyl chain length resulting in the loss of CB7 stabilizing effect and decrease of catalytic efficiency. Existence of two recognition motifs with cationic dioxolanes results in the formation of both 1:1 and 2:1 complexes with different catalytic properties. Keywords: Supramolecular, inclusion complex, kinetic, cucurbituril, hydrolysis, mechanism 1 ACS Paragon Plus Environment

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INTRODUCTION Catalysis in biological systems often involves molecular confinement as a result of supramolecular interactions that sequester substrates in a reaction-ready configuration.[15]

Although the development of synthetic host-guest systems has not reached the level of

enzyme specificity, the characteristics of each synthetic assembly, such as the size, shape, charge, and functional group availability, greatly influence the guest-binding characteristics and have led to remarkable reactivity.[6-13] Supramolecular host-guest assemblies like zeolites,[14] cyclodextrins,[15] calixarenes,[16] carcerands,[17] polymeric assemblies,[18,19] dendrimers,[20] nanocapsules,[21] nanocages,[22] and cucurbiturils[23] have been studied in great detail and have been employed to control chemical transformations. Increased local concentration upon encapsulation of substrates for bimolecular reactions has been exploited for enhanced reactivity inside synthetic hosts. Supramolecular assemblies are able to catalyze cycloadditions by preorganizing substrates.[24-26] In addition to often large rate accelerations, encapsulation in synthetic hosts can alter the reactivity of substrates to produce selectivity otherwise not observed in solution.[27-30] Cucurbit[n]urils (CBn, n=5-8, 10) are a class of aqueous soluble macrocyclic hosts with a rigid hydrophobic cavity and two identical carbonyl-fringed portals.[31-33] As stimuli-responsive properties can be inherited from both the building units and host:guest recognition motifs, this self-assembly strategy enriches the corresponding supramolecular integrities with a broad range or responsiveness and features.[34] CBn ability to sequester molecules into a confined environment allows for an increased chance of collision between reactive units leading to reaction rate acceleration. Catalysis within CBn can be envisioned to occur at two distinct sites, namely, the carbonyl portals and within the hydrophobic cavity. It is critical to recognize that while the catalytic reaction occurs at the rim, the substrates undergoing the transformation might be held in the hydrophobic cavity. Similarly, when the catalytic reaction occurs within the hydrophobic cavity, the rim might play an active role in sequestering the reactants in place for the enhanced reactivity. CBn have been employed as reaction vessel for [3+2] cycloaddition reactions involving cationic alkynes and azide obtaining rate accelerations[35] up to 103-fold in the presence of CB6. This reaction was extensively used to the synthesis of rotaxanes.[36] Cucurbituril-promoted

organometallic

thermal[37]

and

photochemical[38]

reactions were reported by proposing a catalytic cycle in which a ternary complex of 2 ACS Paragon Plus Environment

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ACS Catalysis

metal@CBn@substrate was formed. The active role of CB7 carbonyl portals in influencing reaction pathway was reported from our laboratory on studying the solvolysis of benzoyl chlorides.[39] A nucleophilic assistance was postulated to result from the electrostatic interactions between CB7 and acylium ions resulting in a stabilization of the transition state for the reaction. Hydrolytic reactions taking place via fast substrate protonation equilibria have been reported to be catalyzed by cucurbirturils.[40,41] Catalytic effect being a consequence of protonated substrate stabilization inside cucurbituril because the wellknown pKa shift effect. [41-44] Recently it has been demonstrated that cucurbituril induced pKa shift is not a universal concept but it depends on guest location inside the cavity. This can be achieved by substitution of dimethylamino by diethylamino groups in selected guests, leading to an inversion of the pH dependent selectivity and consequently of the complexation induced pKa shift.[45] Scheme 1. Structures of neutral and cationic dioxolanes. O

O MFD: -CH3 BFD: -CH2(CH2)2CH3 HFD: -CH2(CH2)5CH3 TMAFD: -CH2(CH2)2N+(CH3)3 TEAFD: -CH2(CH2)2N+(CH2CH3)3 O

R

On the basis of these recent results we focus on CB7-mediated hydrolysis of neutral and cationic substrates. Dioxolanes (Scheme 1) bearing an alkyl chain were chosen on the basis of alkyl chain length in order to modify their location inside cucurbituril cavity. In addition cationic dioxolanes bearing a trimethylammonium or a triethylammonium group allow a stronger binding constant to CB7 as well as different location into the host receptor. This reaction is well-documented in the literature to proceed by an A-1 mechanism, where the protonated intermediate breaks down through a unimolecular rate-determining decomposition.[46] The dioxolanes evaluated in this study

are

2-(4-methoxyphenyl)-1,3-dioxolane

(MFD),

2-(4-butoxyphenyl)-1,3-

dioxolane (BFD), 2-(4-heptoxyphenyl)-1,3-dioxolane (HFD), 3-(4-(1,3-dioxolan-2yl)phenoxy)-N,N,N-trimethylpropan-1-aminium bromide (TMAFD) and 3-(4-(1,3dioxolan-2-yl)phenoxy)-N,N,N-triethylpropan-1-aminium bromide (TEAFD). They 3 ACS Paragon Plus Environment

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have adequate size, hydrophobity and charge to be included into the cucurbit[7]uril cavity. Acid hydrolysis for all the dioxolanes is catalyzed when the reaction is taking place inside CB7 cavity with a catalytic effect strongly dependent on both the charge and the alkyl chain length. Preferential incorporation of the alkyl chain inside CB7 cavity affects the distance between cucurbituril portals and the protonation site of dioxolanes.

RESULTS AND DISCUSSION Acid catalyzed reactions that involve formation of carbonium ion intermediate can in principle have a continuous mechanistic spectrum ranging from the A-1 mechanism typical of aliphatic acetal to the SE2 mechanism typical of ortho ester hydrolysis. Reactions that occur by both of these mechanisms are characterized by formation of resonance-stabilized carbonium ion intermediates.[47] The two mechanisms differ in that for the A-1 mechanism carbonium ion formation is the rate-limiting step, while for the SE2 mechanism substrate protonation (perhaps concerted with carbonium ion formation) is the rate limiting step. Dioxolanes hydrolyze[46] by a specific acid A-1 mechanism (Scheme 2) with small negative S≠ values as is frequently observed for acid catalyzed hydrolysis reactions of cyclic compounds.[48] Possible explanations for negative S≠ values in A-1 reactions of cyclic compounds are high solvation of the conjugate acids or transition states, or restriction of rotation about the breaking bond in the transition state.

Scheme 2. Dioxolane hydrolyze by a specific acid mechanism. O

O

O

O

+ H

OH

O +

H 2O

+ H3O+

OR

OR

OH

O

OR

O

H

HO +

OR

+

+

H 2O

H+

HO

OH

OR

Solubility of cationic dioxolanes, TMAFD and TEAFD, facilitates the use of NMR to monitor their hydrolytic process in water (see SI section) confirming the formation of the corresponding aldehyde as a reaction product.

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1. Kinetic studies. Experiments in the presence and absence of CB7 were carried out under pseudofirst order conditions with dioxolane concentration equal to 1.33x10-5M. Acidity was kept constant, pH=5, by using 0.01M acetic acid/sodium acetate buffer. Metal cation binding to CB7 is well-documented in the literature with values of K=130M-1 and K=20M-1 for 1:1 and 1:2 sodium cation complexes.[49]

Simple

calculations show that the percentage of 1:2 complexes preventing the H+ approach to the CB7 portals is smaller than 2% in such a way that the competitive effect of sodium counterions is almost negligible. Figure 1 shows the observed rate constants as a function of CB7 concentration for the different cationic and neutral dioxolanes. A clear catalytic effect is observed for all the dioxolane derivatives. However the catalytic efficiency is strongly dependent on the substituents on the alkyl chain of dioxolanes.

0.06

-1

0.05

k obs / s

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0.05 MFD BFD HFD

TMAFD TEAFD

0.04

0.04

0.03

0.03 0.02

0.02 0.01

0.01 0.00 0.000

0.00

0.001

0.002

0.003

[CB7] / M

0.004

0.005

0.0000

0.0005

0.0010

[CB7] / M

0.0015

0.0020

Figure 1. Influence of CB7 concentration on the pseudofirst order rate constants for dioxolane hydrolysis at pH=5 (acetic acid/sodium acetate buffer). [Buffer]=0.01M; T=25.0⁰C.

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ACS Catalysis

The hydrolysis reactions were also studied as a function of pH. Figure 2 shows the good linear dependence of the observed rate constant with [H3O+] both in the absence and in the presence of 1mM of CB7. 0.004

0.08

0.003

0.06

k obs / s -1

k obs / s -1

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0.002

0.001

0.04

0.02

0

0 0

2.5 x 10-5

5 x 10-5

7.5 x 10-5

10-4

0

2.5 x 10-5

5 x 10-5

7.5 x 10-5

10-4

[H3O+] / M

[H3O+] / M

Figure 2. Influence of [H3O+] upon the observed rate constants for dioxolane hydrolysis in the absence (left) and the presence of 1mM of CB7 (right) at 25.0ºC. () MFD () BFD (▲) HFD. Acidity was fixed with acetic acid /sodium acetate buffers. [Buffer]=0.01M; T=25.0⁰C.

Kinetic results are consistent with a mechanistic scheme (Scheme 3) considering the fast formation of a host:guest complex between the CB7 and the dioxolane (𝐾𝐶𝐵7) where the hydrolytic reaction takes place simultaneously in bulk water and inside the host cavity. This kinetic scheme takes into consideration the simultaneous existence of two well-differentiated environments: water and host (CB7) cavity between which the substrates are distributed. Both reaction pathways, 𝑘𝑤 and 𝑘𝐶𝐵7, involve dioxolane protonation and carbocation formation in the rate determining step. The CB7 assistance for the dioxolane protonation should be the main factor responsible for the catalytic effect observed. Scheme 3. Dioxolane hydrolyze scheme mechanism in water (kw) or CB7 (KCB7 and kCB7).

kw

O

kCB7

H

+

HO

OH

O

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By considering that hydrolysis can take place simultaneously in water, 𝑘𝑤, and the host cavity, 𝑘𝐶𝐵7, it is possible to derive the following rate Equation 1 in terms of pseudofirst order rate constants, 𝑘𝑤 and 𝑘𝐶𝐵7.

𝑘𝑜𝑏𝑠 =

𝑘𝑤 + 𝑘𝐶𝐵7𝐾𝐶𝐵7[𝐶𝐵7]

(1)

1 + 𝐾𝐶𝐵7[𝐶𝐵7]

With cationic dioxolanes the maximum catalytic efficiency is reached with a concentration of 1mM of CB7, while for neutral dioxolanes much higher catalyst concentrations are required. In fact, Figure 1 reveals that 5mM concentrations of CB7 are far from reaching the maximum catalytic efficiency for MFD, BFD and HFD. This experimental behavior is due to the diversity of association constants between CB7 and dioxolanes. These different affinities are well reflected by the binding constants of CB7 with organic cations[50] that range from 105 to 1017 M-1 while much lower values of ≈(102-103) M-1 have been reported for neutral compounds. Table 1 shows the kinetic parameters obtained by fitting Equation 1 to the experimental results (lines in Figure 1). As can be observed dixolane binding constants by CB7 are much higher for cationic than neutral ones, in agreement with previous studies on cucurbituril receptor ability.[31,51] Moreover binding constant for TEAFD is larger than TMAFD reflecting the CB7 recognition ability for tetramethylammonium and tetraethylammonium cations.[52]

Table 1. Kinetic rate constants and host:guest association constants for hydrolysis of dioxolanes in the absence and presence of CB7 at pH=5 and T=25.0⁰C.

Water

CB7

Dioxolane

kw (s-1)

kCB7 (s-1)

KCB7 (M-1)

kCB7 / kw

MFD

(3.40±0.02)x10-4

(1.57±0.03)x10-1

(1.20±0.03)x102

461

BFD

(2.10±0.01)x10-4

(7.30±1.00)x10-2

(1.02±0.21)x102

347

HFD

(3.30±0.02)x10-4

(6.40±0.10)x10-3

(1.10±0.06)x103

19

TMAFD

(2.96±0.01)x10-4

(4.77±0.09)x10-2

(6.60±0.50)x103

160

TEAFD

(2.35±0.01)x10-4

(5.60±0.10)x10-3

(9.60±0.10)x103

24

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More surprising is the catalytic efficiency of CB7 on promoting the dioxolane hydrolysis. Maximum catalytic effects for cationic dioxolanes are 160 and 24 fold for TMAFD and TEAFD respectively despite the large CB7 affinity for TEAFD. Absence of correlation between the CB7 recognition ability and catalytic efficiency is also observed for non-ionic dioxolanes where rate enhancements close to 400-fold were observed for MFD and BFD meanwhile the more hydrophobic substrate shows only a 19-fold rate acceleration. It is worth noting that the CB7 recognition constants for cationic dioxolanes are very small on the basis of expected values[52] for tetramethylammonium (1.2x105 M-1) and tetraethylammonium (1.0x106 M-1). As will be shown these discrepancies are due to a different binding mode operating with cationic dioxolanes. Activation parameters (see Table S1 in SI section) showing negative values for the activation entropy, S≠ =-37.6 cal/mol.K (MFD); S≠ =-36.2 cal/mol.K (BFD) and S≠ =-24.9 cal/mol.K (HFD), are consistent with an A-1 mechanism operating[46] both in bulk water and inside the CB7 cavity. 2. Inhibition by competitive guests. The mechanism of catalytic hydrolysis of dioxolanes through their participation in the formation of an inclusion complex with CB7 can be corroborated by the addition of a competitive guest. The addition to the reaction medium of a guest having a high affinity for CB7 will displace the dioxolane to the aqueous medium and, consequently, the catalytic efficiency will be lost. Figure 3 shows the results obtained by adding tetramethylammonium and tetraethylammonium to a reaction mixture formed by MFD and 1mM of CB7 at pH=5. The observed rate constant decreases with increasing concentration of the added organic cation. For high concentrations of organic cation, where CB7 has been completely saturated, the observed rate constant is compatible with that obtained in pure water for that pH value.

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0.015

0.015

0.01

0.01

k obs / s -1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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k obs / s -1

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0.005

0.005

0

0

0

0.0005

0.001

0.0015

0.002

0

[TMA] / M

0.0005

0.001

0.0015

0.002

[TEA] / M

Figure 3. Influence of tetraalkylammonium chloride concentration on the pseudofirst order rate constants for MFD hydrolysis at pH=5 (acetic acid/sodium acetate buffer) and [CB7]=1mM. (left) Tetramethylammonium and (right) Tetraethylammonium.

Detailed analysis of the tetraalkylammonium inhibitory effect shows that addition of 0.5mM of organic cation results in the loss of almost 90% of catalytic activity. This result suggest multiple complexation between the organic cation and CB7 in such a way that one tetraalkylammonium guest should be shared between two CB7 resulting in the formation of internal and external complexes as have been reported for cationic surfactants.[51] The presence of sodium cations in the reaction media (supplied by the acetate buffer) may facilitate the formation of 2:1 complexes by screening the electrostatic repulsions between the portals of cucurbiturils. Scheme 4 shows the proposed mechanism to explain the inhibitory effect.

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Scheme 4. Mechanistic proposal of the inhibitory effect. Products kw

O

kCB7

O

KCB7

O

O

+

O

Me

O

+

Me

K1

K2 +

Experimental results agree with mechanistic proposal shown in Scheme 4 (curves in Figure 3) where the dioxolane binding constant to CB7, as well as the kinetic parameters showed in Table 1 have been used. Competitive complexation of tetramethylammonium and tetraethylammonium have been modulated by using the values of K1=(1.2±0.4)x105 M-1 and K1=(1.0±0.2)x106 M-1 previously reported for TMA and TEA respectively.[52] Additionally optimized binding constants for the 2:1 complexes, K2=(36±13)x103 M-1 and K2=(12.0±3.2)x103 M-1 have been obtained. Tentative use of simple complexation models (1:1 for both CB7:dioxolane and CB7:tetraalkylammonium considering the possibility of ternary complexes 1:1:1 for CB7:tetraalkylammonium:dioxolane) fail to explain the experimental results as is shown in the SI section. 3. Computational results. The mechanism for acid catalyzed dioxolane hydrolysis is considered to proceed by an A-1 mechanism.[46] Protonation could become partially rate determining if the energy for the protonation transition state were increased by reducing basicity of the energy corresponding to the bond-breaking step were reduced by increasing the ease of C-O bond breaking. The proposed mechanism for dioxolane hydrolysis in the presence of CB7 involves the substrate protonation in the host:guest complex and its evolution to carbocation.

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ACS Catalysis

Figure 4 shows the molecular electrostatic potential (MEP) plots on the electronic density surface with contour value of 0.01 a.u. for the CB7 and 0.03 a.u. for MFD, BFD and HFD. This MPEs indicates that inside the cavity there is a large negative potential (red regions), which provides a stabilizing electrostatic situation to interact with positive charges. Outside the CB7 molecule, there is a large positive potential (shown in blue color). The guests present two regions of negative potential, in which both are due to oxygen atoms: at the head (dioxolane group) and at the phenoxy group, in the tail of the guest molecule. These regions cause a repulsive interaction with the interior of CB7 cavity, since it also have a negative potential. That is probably the reason for the minima structures of Figure 4-right, in which these oxygen atoms lies at the border of the cavity.

Figure 4. (left) Electrostatic potential plots on the electronic density surface with contour value of (a) 0.01 for CB7 (top, frontal, perspectives angles) and (b) 0.03 for MFD, BFD and HFD molecules. (Righ) Frontal view of the optimized structures of host:guest complexes formed by CB7 and MFD, BFD and HFD.

Geometrical deformation of the host and the guest after the complexation was very small in all cases, as can be seen by the lower preparation energy, Eprep, and the almost unchanged internal and external diameter and height (Table S2A, in SI section). The CB7 is a rough D7h distorted structure (Table S2B in SI section). Attempts to optimize the CB7:BFD and CB7:HFD structures with the guest tail interacting with the host cavity were also performed. In all trials, the energies were found to be at least 10 and 20 kcal/mol higher than the minima structures shown in Figure 4. Figure 5 shows the relative energies of structures along the A-1 pathway for dioxolane hydrolysis. The optimized structures for the CB7:dioxolane host:guest complexes (step B in Figure 5) result in a stabilization factor of 15.4kcal/mol 11 ACS Paragon Plus Environment

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independently of the alkyl chain length (see SI section). In step C of the reaction coordinate the H3O+ ion is bound to the CB7:dioxolane complex. The hydronium ion lies above the dioxolane group, performing three hydrogen bonds, one with the oxygen atom at the head of the guest, and another two with the carbonyl groups of the host structure. This 1:1:1 complex corresponds to the minimum energy along the reaction pathway for MFD and BFD. There is almost no change in the position of MFD on going from CB7:MFD to CB7:MFD:H3O+ complexes. For BFD and HFD, the guest moves the dioxolane head outside the cavity in order to interact with the hydronium ion.

Figure 5. Relative energies of intermediate compounds for MFD acid hydrolysis in the presence of CB7.

Optimized minima energy structure for the protonated dioxolane included into cucurbituril cavity, CB7:MFD-H+, is shown in step D of Figure 5. In this step the proton was transferred to the guest molecule, and a water molecule was released. The proton is bound to an oxygen atom of the dioxolane ring. The protonated oxygen atom points to carbonyl groups of the CB7 moiety, suggesting the formation of a hydrogen bond. The last step of the A-1 mechanism corresponds to the dioxolane ring opening and formation of carbocation species, CB7:MFD+. In all cases, the opened ring goes out the host cavity, forming hydrogen bond with the carbonyl group. The EDA-NOCV energy terms (in kcal/mol) for complexes CB7:MFD; CB7:BFD; CB7:HFD; CB7:MFD+; CB7:BFD

+

and CB7:HFD+, related to the first

and last studied stationary compounds, steps A and E (see Figure 5), considering the 12 ACS Paragon Plus Environment

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ACS Catalysis

CB7 host and MFD+; BFD + and HFD+ guests as interacting fragments are reported in Table 2. The host:guest interaction in complexes of step A is weaker than the host:guest interactions in systems of step E, as shown by the Eint values. This means that the carbocation species described by CB7:MFD+ and CB7:HFD+ are interacting much more strongly with the CB7 cavity than the CB7:MFD and CB7:HFD analogues. This is mainly due to the hydrogen bond formation with the CO-H group of the opened dioxolane ring and the carbonyl group of the host. The Eint values do not change in a significant way on going from CB7:MFD; CB7:BFD and CB7:HFD to CB7:MFD+; CB7:BFD+ and CB7:HFD+. For instance, Eint for CB7:MFD; CB7:BFD and CB7:HFD ranged from -28.9 to -30.2 kcal/mol, whereas for CB7:MFD+; CB7:BFD+ and CB7:HFD+ the Eint ranged from -77.9 to -84.7 kcal/mol. The preparation energy (Eprep) indicates that there is almost no changes in the CB7:MFD; CB7:BFD and CB7:HFD structures before and after the complexation, whereas in CB7:MFD+; CB7:BFD+ and CB7:HFD+, a bit more energy is necessary in order to prepare the fragments for the interaction. The largest Eprep values for complexes in step A is 1.7 kcal/mol (CB7:HFD) and for complexes in step E is 5.8 kcal/mol (CB7:HFD+), corresponding to the large guests. In complexes CB7:MFD; CB7:BFD and CB7:HFD, the Edisp is the main stabilizing energy term (ca. 60%), showing that the weak long-range dispersion stabilization is the most important contribution to the total interaction energy. Electrostatic interactions and orbital interactions contribute about 22 an 16%, as shown by Velstat and Eorb energy terms. Slight more stabilizing Edisp and Eorb are seen in the host:guest complex CB7:HFD, whereas the large stabilizing value for Velstat is seen for CB7:MFD. Complex CB7:BFD presents the intermediate values. Such tendencies follow the increase of guest structure in the order MFD; BFD and HFD. For instance, the Edisp ranged from -40.6 to -41.9 kcal/mol (CB7:MFD and CB7:HFD), the Velstat ranged from -14.7 to -15.3 kcal/mol (CB7:HFD and CB7:MFD), and Eorb ranged from -10.9 to -11.4 kcal/mol (CB7:MFD and CB7:HFD).

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Page 14 of 36

Table 2. EDA-NOCV energy terms (in kcal/mol) for complexes CB7:MFD+; CB7:BFD+ and CB7:HFD+, considering the CB7 (host) and MFD+; BFD + and HFD+ (guests) as interacting fragments. step A step E CB7:MFD

CB7:BFD

CB7:HFD

CB7:MFD+

CB7:BFD+

CB7:HFD+

ΔEint

-28.9

-30.0

-30.2

-77.9

-83.1

-84.7

ΔEprep

1.6

1.6

1.7

4.7

5.2

5.8

ΔEPauli

37.9

37.8

37.8

52.0

57.0

61.2

ΔVelstat

-15.3(22.9%)

-14.8 (21.8%)

-14.7 (21.6%)

-66.0 (50.8%)

-68.9 (49.2%)

-69.6 (47.7%)

ΔEorb

-10.9 (16.4%)

-11.3 (16.6%)

-11.4 (16.7%)

-29.0 (22.3%)

-29.1 (20.8%)

-30.1 (20.6%)

ΔEdisp

-40.6 (60.7%)

-41.8 (61.6%)

-41.9 (61.6%)

-35.0 (26.9%)

-42.1 (30.0%)

-46.3 (31.7%)

ΔEorb

1

-0.8

-0.7

-0.7

-5.0

-5.1

-4.8

ΔEorb2

-0.7

-0.7

-0.7

-2.5

-2.2

-2.2

ΔEorb

3

-0.7

-0.7

-0.7

-2.3

-2.0

-2.1

ΔEorb

4

-0.6

-0.6

-0.6

-1.3

-1.3

-1.3

ΔEorb5

-0.5

-0.5

-0.5

-1.4

-1.2

-1.2

ΔEorb6

-0.4

-0.4

-0.4

-0.7

-1.0

-1.0

ΔEorb

7

-0.4

-0.4

-0.4

-0.8

-0.8

-0.9

ΔEorb8

-0.3

-0.3

-0.3

-0.8

-0.8

-0.8

ΔEorb9

-0.3

-0.3

-0.3

-0.8

-0.7

-0.7

ΔEorb

10

-0.3

-0.3

-0.3

-0.7

-0.6

-0.6

ΔEorbres

-5.9

-6.3

-6.5

-12.8

-13.3

-14.5

qguest(a)

-0.013

-0.013

-0.014

0.882

0.884

0.884

qhost(a)

0.013

0.013

0.014

0.118

0.116

0.116

(a)Hirshfeld

charge analysis[53,54] of the guest and host fragments

In complexes CB7:MFD+; CB7:BFD+ and CB7:HFD+, the Velstat is the main component of the interaction (ca. 50%), followed by the Edisp (30%) and Eorb (20%) energy terms. Both Edisp and Eorb are considerably more stabilizing in the carbocation guest complexes than in the neutral ones, as a direct consequence of the hydrogen bond between the CO-H group of the guest and the carbonyl groups of the host. Larger steric repulsions are seen for CB7:MFD+; CB7:BFD+ and CB7:HFD+ than for CB7:MFD; CB7:BFD and CB7:HFD, as shown in the EPauli term, as a direct large orbital interactions. The Hirshfeld charge analysis also indicates that there is more charge transfer in host:guest systems of step E (ca. 0.1 e) than those of step A (ca. 0.01 e), following the same tendency of orbital energy term. The magnitude of Edisp is very similar among complexes of step A and E. Larger interaction is seen for the larger

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ACS Catalysis

guests, probably due to the tail guest interaction with the host cavity border, which provides further stabilization to the Eint. The relative energies of intermediate compounds (steps A-E) are shown in SI section. As previously the sum of the electronic energy of the reactants: CB7; (MFD or BFD or HFD) and H3O+ was taken as reference (0 kcal/mol). The difference in the electronic energy on going from step A to step B is virtually the same, indicating that the formation of the host:guest complex bring the same stabilization for all systems (around 15 kcal/mol). From step B to C, a large difference is noticed: The CB7:MFD:H3O+ is much more stable than CB7:BFD:H3O+ and CB7:HFD:H3O+, following the same tendency of guest getting out the cavity. These findings also agree with the MEPs in which the guests BFD and HFD are with their phenoxy oxygen atom inside the CB7 cavity, providing a high destabilization of the system, since the chargelike character of the oxygen atom and the host cavity (see red regions in Figure 4). The relative energies of the host:guest complexes of step D are again very close one another, only with CB7:BFD-H+ a bit destabilized in relation to CB7:MFD-H+ and CB7:HFDH+. This higher energy could also be related to the guest BFD being more out of the cavity than MFD and HFD. Because the different stabilization of the ternary complexes (CB7:dioxolane:H3O+), the barrier of step C-D are 19.8, 7.9 and -1.5 kcal/mol. The last step, E, again let the relative energy of the different guests very similar one another. Computational analysis show that distance between CB7 carbonyl portals and dioxolane moiety in the host:guest complexes are independent of alkyl chain length for neutral species. However this distance is modified by incorporation of ionic species both in the ternary complex formed by CB7:dioxolane:H3O+ or in the binary complex formed by CB7 and the protonated dioxolane as well as in the binary complex formed by CB7 and the carbocation derivative. In all these situations the distance between the cucurbituril portal and the dioxalane derivative guest increases with the alkyl chain length. Consequently the stabilization of the transition state supported by the host:guest complex should decrease on increasing the length between the dioxalane moiety and the CB7 portal, resulting in a loss of the catalytic efficiency (kCB7/kw = 461; 347 and 19 for MFD; BFD and HFD respectively). 4. Cationic dioxolanes. In Figure 1 shows the clear catalytic efficiency of CB7 on promoting the hydrolysis of cationic dioxolanes, TMAFD and TEAFD. However application of mechanistic model showed in Scheme 3 (kinetic rate Equation 1) results 15 ACS Paragon Plus Environment

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Page 16 of 36

in very low binding constants for these cationic derivatives (102 fold smaller than expected on the basis of tretraalkylammonim binding constants to CB7). Consequently the mechanism of supramolecular catalysis for these cationic guests should be revised by taking special care in the characterization of the CB7:dioxolane host:guest complexes. Detailed analysis of the complexation mode was obtained by computational analysis. Three different initial guess for geometry optimization were carry out. In the first scheme the dioxolane oxygen atoms of guests TMAFD and TEAFD were inserted exactly in the plane formed by the carboxyl groups of the CB7 host, resulting in the minima structures TMAFD-I and TEAFD-I. The starting host-guest geometries of the second scheme were considered as phenoxy oxygen at the curcubituril carboxyl level, resulting in TMAFD-II and TEAFD-II, and the last scheme were done by considering as the starting point the amine group of the hosts at the carboxyl plane of curcubituril host, resulting in complexes TMAFD-III and TEAFD-III.

TMAFD-I E=0.7 kcal/mol

TMAFD-II E=3.2 kcal/mol

TEAFD-I E=11.3 kcal/mol

TEAFD-II E=12.7 kcal/mol

TMAFD-III E=0.0 kcal/mol

TEAFD-III E=0.0 kcal/mol

Figure 6. Minima structures of complexes TMAFD-I to TEAFD-III, including the energy relative to isomer more stable (in kcal/mol).

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ACS Catalysis

The minima structures of complexes TMAFD-I to TEAFD-III, and their relative energy are shown in Figure 6. In all cases, the most stable isomers are TMAFD-III and TEAFD-III, in which the charged amine group is inside the curcubituril cavity. For complexes of guest TMAFD, the host-guest TMAFD-III is only 0.7 kcal/mol more stable than TMAFD-I, and 3.2 kcal/mol more stable than TMAFD-II. On the other hand, TEAFD-III is much more stable than its isomers. For instance, it is 11.3 kcal/mol more stable than TEAFD-I and 12.7 kcal/mol more stable than TEAFD-II. Note that –OCH2– group is closer to the carbonyl portals of CB7 for TMAFD-III than for TEAFD-III. Formation of host:guest complexes between CB7 and trialkylammonium dioxolanes was established by using 1H NMR spectroscopy. Valuable information about the structure and stoichiometry of the complexes can be obtained from the complexation-induced chemical shifts changes (=bounded-free) of the proton resonances of the guest molecules. Upfield shifts (0) of the guest protons are associated with proximity to host carbonyl oxygen atoms.[55-58] The addition of CB7 to TEAFD lead to the expected upfield shifts (see Figure 7).

Figure 7. 1H NMR spectra of TEAFD with and without different molar ratios of CB7.

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Page 18 of 36

A detailed analysis indicated that positive effects (>0) were observed for hydrogen atoms in the –OCH2– group of the dioxolane (TMAFD or TEAFD, see Table 3). All other signals in the alkyl chain of the dioxolanes showed different upfield effects (small negative  values, see Table 3) as a result of the cationic moiety of the dioxolane being included in the CB7 cavity.

Table 3. CB7-induced chemical shifts (=bounded-free) of the 1H resonances of the OCH2, CH2, NCH2 and NCH2CH3 for different host–guest molar ratios. δ TMAFD (ppm)

[CB7]:[Diox]

 TEAFD (ppm)

OCH2

CH2

NCH2

CH3

OCH2

CH2

NCH2

CH3

1:2

0.06

-0.08

-0.15

-0.11

0.04

-0.07

-0.15

-0.07

1:1

0.08

-0.20

-0.36

-0.22

0.05

-0.12

-0.29

-0.15

2:1

0.07

-0.11

-0.17

-0.12

0.05

-0.08

-0.21

-0.12

However, guest signals kept shifting when CB7 increased above an equimolar concentration; this indicated the formation of complexes other than those with a 1:1 ratio. Clear upfield shifts are observed for methylene hydrogen atoms in the main chain (NCH2) of dioxolane reaching a value of =-0.36ppm for 1:1 stoichiometric mixture of CB7 and dioxolane. The magnitude of the upfield shift decrease on increasing the percentage of CB7 in the mixture, =-0.17ppm for 2:1 ratio of CB7:dixolane. This decrease in the magnitude of the upfield shift is not compatible with formation of just 1:1 complexes because  should reach a constant value once all the dioxolane is forming the host:guest complex. The only explanation is by considering the incorporation of a second cucurbituril host resulting in the formation of a 2:1 complex. The approach of a second CB7 molecule causes the CB7 of the 1:1 complex to move along the alkyltrimethylammonium group to minimize the repulsions between the portals of the host. This situation is consistent with a change in the magnitude of the upfield shift observed on going from the 1:1 to the 2:1 complex. Formation of 2:1 host:guest complexes, each of which are formed as an inclusion complex with two CB7 molecules have been reported for Thioflavin T[59] and Sanguinarine.[60] Formation of both 1:1 and 2:1 complexes between CB7 and TMAFD or TEAFD should be considered in the mechanism for dioxolane hydrolysis in the 18 ACS Paragon Plus Environment

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ACS Catalysis

presence of cucurbituril. Scheme 5 shows the mechanistic proposal where TMAFD forms 1:1 (K1:1) and 2:1 (K2:1) complexes with CB7 and hydrolysis takes place simultaneously in bulk water (kw), in the 1:1 (k1:1) and the 2:1 (k2:1) complexes. Rate Equation 2 can be derived for the dependence of the observed rate constant, kobs, with the CB7 concentration. Scheme 5. The mechanistic proposal where forms 1:1 and 2:1complexes. O

N+

H

kw

H O +

O

+

O

HO

OH

k2:1

k1:1

K1:1

H O +

O

K2:1

O

O

N+

𝑘𝑜𝑏𝑠 =

H O +

O

O

N+

N+

𝑘𝑤 + 𝐾1:1𝑘1:1[𝐶𝐵7] + 𝐾1:1𝐾2:1𝑘2:1[𝐶𝐵7]2 1 + 𝐾1:1[𝐶𝐵7] + 𝐾1:1𝐾2:1[𝐶𝐵7]2

(2)

Note that [CB7] refers to the concentration of uncomplexed cucurbituril. Under the experimental conditions used in the present study the inequality [CB7]>>[Dioxolane] is not verified, implying that concentration of uncomplexed cucurbituril should be different from total concentration of the host, [CB7]≠[CB7]T. Concentration of uncomplexed cucurbituril can be obtained by solving the following third order Equation 3 (see for derivation in SI section). 𝐾1:1𝐾2:1[𝐶𝐵7]3 + {𝐾1:1 ― 𝐾1:1𝐾2:1[𝐶𝐵7]𝑇 + 2𝐾1:1𝐾2:1[𝐺]𝑇}[𝐶𝐵7]2 + {1 + 𝐾1:1[𝐺]𝑇 ― 𝐾1:1[𝐶𝐵7]𝑇}[𝐶𝐵7] ― [𝐶𝐵7]𝑇 = 0

(3)

For the fitting procedure the hydrolysis rate constants in bulk water, 𝑘𝑤, as well as the binding constants for the 1:1 complex were kept constant by using the values experimentally obtained and those reported in the literature respectively. Figure 1 (and Figure S16 in SI section) shows the very good fit of kinetic data obtained for TMAFD and TEAFD (kinetic parameters are reported in Table 4). It should be noted that 19 ACS Paragon Plus Environment

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Page 20 of 36

binding constants and rate constants for the 2:1 complexes are very close to those previously obtained just considering the formation of 1:1 complexes. According to Scheme 5 cationic dioxolanes are able to accommodate two host implying that two rate constants should be considered for the cucurbituril catalyzed dioxolane hydrolysis. Table 4. Kinetic rate constants and host:guest binding constants fro hydrolysis of dioxolanes in the presence of CB7 at pH=5 and T=25.0°C. according to Scheme 5 and Equations 2-3.

𝒌𝒘 / 𝒔 ―𝟏

𝒌𝟏:𝟏 / 𝒔 ―𝟏

𝒌𝟐:𝟏 / 𝒔 ―𝟏

𝐊𝟏:𝟏 / 𝑴 ―𝟏

𝑲𝟐:𝟏 / 𝑴 ―𝟏

TMAFD

2.96x10-4

(1.00±0.1)x10-2

(4.90±0.1)x10-2

1.20x105

(4.30±0.5)x103

TEAFD

2.35x10-4

(7.00±2.0)x10-4

(5.50±0.1)x10-3

1.00x106

(11.0±2.0)x103

Rate constant for the 1:1 complex, 𝑘1:1, is always smaller than for the 2:1 complex , 𝑘2:1 , in agreement with the first CB7 being mainly located at the cationic moiety of the dioxolane. Inclusion of trialkylammonium group of dioxolane into the CB7 cavity forming the 1:1 host:guest complex implies that CB7 is far away for the reaction moiety where protonation takes place, i.e. the dioxolane ring. This large distance between CB7 and the protonated moiety of dioxolane implies a lack of the supramolecular catalytic effect. Difference between 𝑘1:1 and 𝑘2:1 is smaller in TMAFD than in TEAFD in agreement with the smaller difference in energy between the two possible structures for the 1:1 complex. In the first case, the difference in energy between placing the CB7 in the cationic group (TMAFD-I and TEAFD-I) or the dioxolane ring (TMAFD-III and TEAFD-III) is small (see Figure 6) and, therefore, the CB7 can assist the hydrolysis of TMAFD the 1:1 complex. Broadering of NMR signals upon complexation do not allow differentiating the binding mode of TMAFD and TEAFD. Previous studies on CB7 inclusion of alkyltrimethylammonium and alkyltriethylammoniun groups show the formation of distinct structures for the 1:1 complexes.[61] In the case of alkyltrimethylammonium cations, the CB7 portal is close to the trimethylammonium moiety, whereas for alkyltriethylammonium cations the triethylammonium moiety inside the CB7 cavity. This experimental behavior is also reflected by the theoretical calculations as can be observed in Figure 6.

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ACS Catalysis

CONCLUSIONS Catalytic efficiency in dioxolane hydrolysis in the presence of CB7 is strongly dependent on the substituents on the alkyl chain, length of the neutral alkyl chain and/or nature of the cationic group. Dioxolanes hydrolyze by a specific acid A-1 mechanism where carbonium ion formation is the rate-determining step. Catalysis occurs at the host carbonyl portals with the substrate hold into the hydrophobic cavity. In analogy to organometallic reactions a ternary complex dioxolane@CB7@H3O+ is formed along the reaction pathway, where the hydronium ion lies above the dioxolane group performing three hydrogen bonds: one with the oxygen atom at the head of the guest and another two with the carbonyl groups of the host. Next step proton is transferred to dioxolane and a water molecule being released. The protonated oxygen atom points to carbonyl groups of the CB7 moiety, suggesting the formation of hydrogen bond. It should be noted that these complexes are not stable in the absence of CB7. Last step corresponds to the dioxolane ring opening and formation of the carbocation specie. In all the cases, the opened ring goes out the host cavity, forming hydrogen bond with the carbonyl group. Distance between the CB7 carbonyl portals and dioxolane moiety in the host:guest complex are independent on the alkyl chain length for neutral species. However this distance is modified by formation of the ternary complex dioxolane@CB7@H3O+ as well as in the binary complex formed by CB7 and the protonated dioxolane or the carbocation derivative. In all these situations the distance between the cucurbituril portal and the dioxolane derivative guest increases with the alkyl chain length. Consequently the stabilization of the transition state supported by the host:guest complex should decrease on increasing the distance between the dioxolane group and the CB7 portal, resulting in a loss of the catalytic efficiency (kCB7/kw = 461; 347 and 19 for MFD; BFD and HFD respectively). Cationic

dioxolanes

bring

two

recognition

motifs

for

CB7:

the

trialkylammonium group and the dioxolane ring. Supramolecular catalysis is due to formation of 1:1 and 2:1 host:guest complexes with the first cucurbituril group being located in the cationic group of the guest. Inclusion of the triethylammonium group inside the CB7 cavity for the TEAFD derivative results in a large distance between the CB7 portals and the dioxolane moiety in the 1:1 complex. This distance is responsible for the very low catalytic effect (just 3-fold) in comparison with bulk water. Catalytic 21 ACS Paragon Plus Environment

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efficiency

is

increased

on

going

to

the

Page 22 of 36

2:1

complex.

Complexation

of

trimethylammonium group by CB7 is less effective than triethylammonium with the CB7 being distributed between the cationic moiety (just 0.7 kcal/mol more stable) and the dioxolane ring in TMAFD. This very small difference in stability allow the CB7 to stabilize the protonated dioxolane in the 1:1 complex resulting in a 33-fold catalytic effect on going form bulk water to the 1:1 complex. Incorporation of a second CB7 unit results in a modest (5-fold) increase of the catalytic efficiency. EXPERIMENT SECTION CB7 was synthesized by using the procedure described by Nau et al.,[62] and after separation of CB7 from others homologues, the sulfuric acid was exchanged with chlorhydric acid by dissolving the product in concentrated HCl, diluted with water, and precipitated with acetone. This procedure was repeated two times and finally the product was dissolved in water and precipitated several times with acetone until the pH of the solution was neutral as seen by indicator paper. Finally the product was dried on high vacuum at 140ºC for several days. The pH of a 5 mM solution was checked with a glass electrode and was found to be 5.7. The product was characterized by proton nuclear magnetic resonance and electrospray ionization mass spectrometry based on known literature data.[63] Synthesis of dioxolanes. 2-(4-methoxyphenyl)-1,3-dioxolane (MFD) was synthesized following Fife and Jao’s method.[46]Subsequently, 2-(4-butoxyphenyl)-1,3-dioxolane (BFD), 2-(4-hepthoxyphenyl)-1,3-dioxolane (HFD), TMAFD and TEAFD were synthesized in two steps. First, the ethers were synthesized according to the method of Salmoria et al. and second step was equal to the technique used to prepare the MFD.[64] In the procedure for BFD, 4.8 mL of bromobutane (or 7.6 mL of bromohepthane to HFD, or 5 mL of 1,3-dibromopropane to TMAFD and TEAFD) were initially mixed with 5.0 g of 4-hydroxybenzaldehyde (Sigma-Aldrich, 98%) and 11.2 g of potassium carbonate (Vetec, 99 %), and 30.0 ml of 2-butanone (Sigma-Aldrich, 99%) in round bottom flasks of 250 mL and allowed to react under reflux for 14 hours. So, the reaction mixtures were filtered hot to remove the potassium carbonate and the solvent was removed using a rotary evaporator. Then 5 mL of the oils obtained in this step and 5 mL of 4-methoxybenzaldehyde (for MFD) were added to 6 mL of ethylene glycol (Vetec, 99.5%), 60 mL of toluene (Vetec, 99%) and 250 mg of 4-toluenesulfonic acid were charged into 250 mL round-bottomed flasks and allowed to react under reflux for 5 h. 22 ACS Paragon Plus Environment

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The water produced during the reaction being removed by a Dean-Stark trap. The mixtures were washed with 100 mL of a 1.0 mol L-1 solution of potassium hydroxide (Vetec, 85%) and separated. During this procedure there was the formation of emulsion, rapidly broken with the addition of hexane (Vetec, 95%). The organic phase was collected, dried with anhydrous sodium sulfate (Vetec, 99%), filtered and the solvent was removed on a rotary evaporator. One portion of product with 1,3-dibromopropane react with trimethylamine soluction 35% (m/m) to form TMAFD and other portion react with triethylamine to form TEAFD. The oils were left for 30 min. under vacuum in liquid nitrogen trap. MFD (Yield: 85.7 %): 1H NMR – 200.00 MHz, 0.1 mol.L-1 in CDCl3, reference: TMS – (S1) δ, (ppm): 3.8 (s, 3H), 4.12 (m, 4H), 5.76 (s, 1H), 6.9 (d, 2H, J=8.1 Hz), 7.4 (d, 2H, J=8.1 Hz). Analysis method for GC-MS for dioxolanes: heating was set at 60 °C for 5 min., followed by ramp from 30 °C/min. to 300 °C and maintained for 5 min. at this temperature (detector in scan mode between 60 m/z and 600 m/z). Chromatogram obtained with single signal in tR = 10.11 min., and fragmentgram obtained (S2) with m/z 179 (M-1) 100 %, m/z 180 (M) 23.7 %, m/z 181 (M+1) 4.2 %. BFD (Yield: 78.9 %): 1H NMR – 200.00 MHz, 0.1 mol.L-1 in CDCl3, reference TMS – (S3) δ, (ppm): 0.97 (t, 3H, J = 6.1 Hz), 1.50 (m, 2H), 1.76 (m, 2H), 3.98 (t, 2H, J = 6.1 Hz), 4.09 (m, 4H), 5.75 (s, 1H), 6.89 (d, 2H, J = 8.1 Hz), 7.39 (d, 2H, J = 8.1 Hz). GC-MS with method described for the MFD. Chromatogram obtained with single signal in tR = 11.35 min., and fragmentgram obtained (S4) with m/z 221 (M-1) 100 %, m/z 220 (M) 28.2 %, m/z 219 (M+1) 6.5 %, m/z. HFD (Yield: 82.6 %): 1H NMR – 200.00 MHz, 0.1 mol.L-1 in CDCl3, reference TMS – (S5) δ, (ppm): 0,89 (t, 3H, J=6.1 Hz), 1.30 (s, 8H), 1.75 (m, 2H), 3.95 (t, 2H, J=6.1 Hz), 4.12 (m, 4H), 5.75 (s, 1H), 6.89 (d, 2H, J=8.1 Hz), 7.38 (d, 2H, J=8.1 Hz). GC-MS with method described for the MFD. Chromatogram obtained with single signal in tR = 12.58 min., and fragmentgram obtained (S6) com m/z 263 (M-1) 100 %, m/z 264 (M) 39.1 %, m/z 265 (M+1) 5.1 %. TMAFD (Yield: 65.6 %): NMR, 0.1 mol.L-1 in CD3CN, reference TMS – 1H 400.00 MHz (S7) δ, (ppm): 2.25 (m, 2H), 2.76 (s, 9H), 3.58 (t, 2H), 3.95 (t, 2H), 4.12 (m, 4H), 5.66 (s, 1H), 6.96 (d, 2H, J = 8.8 Hz), 7.87 (d, 2H, J = 8.8 Hz).

13C

100.00

MHz (S8) δ, (ppm): 23.01 (CH2), 52.98 (NCH3), 59.01 (NCH2), 63.81 (OCH2), 65.07 (C1), 103.26 (C2), 114.42 (C3), 117.42 (C4), 128.13 (C5), 159.19 (C6).

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TEAFD (Yield: 70.1 %): NMR, 0.1 mol.L-1 in CD3CN, reference TMS – 1H 400.00 MHz (S9) δ, (ppm): 1.25 (t, 9H, J = 7.2 Hz), 2.10 (m, 2H), 3.26 (q, 8H, J = 7.4 Hz), 3.63 (t, 2H), 3.95 (t, 2H), 4.08 (m, 4H), 5.66 (s, 1H), 6.95 (d, 2H, J = 8.8 Hz), 7.87 (d, 2H, J = 8.8 Hz).

13C

100.00 MHz (S10) δ, (ppm): 6.73 (CH3), 21.64 (CH2), 52.77

(NCH2), 64.26 (NCH2), 64.90 (OCH2), 64.92 (C1), 103.16 (C2), 114.11 (C3), 117.18 (C4), 127.97 (C5), 159.00 (C6). The spectra of Nuclear Magnetic Resonance (NMR) were performed on a Bruker 200.00 MHz spectrometer, operating with 1H detector (200.00 MHz) and adjusted with MestRe-Nova 6.0.2 software. Tetramethylsilane (TMS, Cambridge Isotope Laboratories, 99.9 %) was used as the internal reference for the 1H NMR analyzes in organic solvent (Chloroform-CDCl3). Chromatograms and fragmentgrams were obtained by gas chromatography coupled to mass spectrometry (GC-MS). A Shimadzu GC-17A chromatograph equipped with a column DB-5 (Agilent) 30 m, interfaced to a workstation with a GC-MS data acquisition and processing system version 1.20 (LabSolution, 2004) was used. Hydrolysis of dioxolanes. The acid hydrolysis of the dioxolanes (MFD, BFD, HFD, TMAFD and TEAFD) was performed in aqueous solution and the formation of 4alkoxyphenylbenzaldehyde was monitored by UV/Vis spectroscopy at the wavelength of λ = 286 nm. For each kinetic measure, solutions containing from 0 to 5.0 mmol.L-1 of cucurbituril (CB7) and acetic acid/sodium acetate buffer 0.01 mol.L-1 and pH = 5.0 were added in a 3.0 mL quartz cell in temperature of 25°C. The reactions were initiated by the addition of 10.0 μL of substrate’s solution (2.0x10-3 mol.L-1) in acetonitrile, so that the initial concentration of the dioxolanes in the cell was 1.33x10-5 mol.L-1. Subsequently, measurements were made as a function of pH (in the range of 4.0-5.0) and temperature (varied temperature of 15-45 °C) and N(R)4Br concentrations. Absorbance determinations were performed on a Cary 50 spectrophotometer coupled to a microcomputer, with a Cary Win UV 3.00 program for UV/Vis spectra storage coupled to a Varian PCB 1500 thermostatic bath with Peltier water system. The equipment allows to analyze results as a function of time and calculate the rate constants. Quartz cells with 1.0 cm of optical path and capacity for 3.0 mL of solution were used. Computational calculations. Theoretical approaches reporting the bonding properties of several hydrocarbons interacting with CB6/CB7 hosts were recently reported.[65,66] In 24 ACS Paragon Plus Environment

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these supramolecular systems, the proper modelling of the London dispersion energy is crucial to describe their binding properties, since the dispersion and hydrophobic interactions play a central role, stabilizing such host-guest systems.[65-67] Therefore, in this work, all structures were optimized with no restrictions at DFT framework, by employing the Becke86[68] and the Perdew88[69] exchange-correlation functional, in conjunction to the Grimme’s D3 empirical dispersion correction[70-73] and the Becke-Johnson damping functions,[74,75] BP86-D3(BJ). The triple- quality TZ2P[76] Slater type basis set was employed. The water solvation effects were implicitly taken into account by employing COSMO solvation model.[77] The structures were verified as minima on the PES through the analytical second derivatives analysis.[78-80] Geometry optimization and vibrational analysis were performed at ADF v2016 software package.[81-83] The BP86-D3 choice was based in our previous work, in which the chosen level of theory was found to be computationally feasible and successful to describe the molecular geometries of weak non-covalently bonded host-guest complexes when compared to the experimental/high level DFs/ab-initio methods.[84-86] It was made three different relaxed scam analysis between MFD-MFD+ and in the host-guest system CB7:MFD - CB7:MFD+ (steps A-E). The first scam is related to the hydronium getting close to the methoxy oxygen; in the second scam the proton is exchange to the dioxolan oxygen; and the third scam is related to the dioxolan ring opening, forming the carbocation. All the scams (30-50 steps each) were made using the low-cost level HF-3C,[87] at ORCA 4.0 software package.[88] The maxima points in the scam surface were then optimized to TS at Gaussian 09 software package,[89] at BP86/Def2-TZVPP level of theory.[90,91] The energy of these TS points, characterized by a single imaginary vibrational frequency, were made in ADF software at BP86D3(BJ)/TZ2P level of theory, including solvent effects (water) with the COSMO model. The physical nature of host-guest interactions in MFD, MFD+, BFD, BFD+, HFD and HFD+ were verified through the canonical energy decomposition analysis EDA-NOCV,[92] which combines the Extended Transition State (ETS)[93] and the Natural Orbitals for Chemical Valence (NOCV)[94] methods, at BP86-D3(BJ)/TZ2P level of theory in the ADF software.

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ASSOCIATED CONTENT Supporting Information Copies of 1H NMR, 13C NMR, GC-MS analysis, kinetic experiments and considerations for computational calculations.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] * E-mail: [email protected]

ORCID Luis Garcia-Rio: 0000-0003-2802-8921 Faruk Nome: 0000-0001-8864-6807

Notes The authors declare no competing financial interests

ACKNOWLEDGMENTS To our deep sorrow our colleague and friend Faruk Nome passed away during the last steps of the preparation of this paper. We would like to dedicate this work to his memory The authors thank Brazilian funding from CNPq, CAPES and FAPESC, and CEBIME (UFSC) for HRMS analysis; and financial support from Ministerio de Economia y Competitividad of Spain (Project Nos. CTQ2014-55208-P and CTQ2017-84354-P), Xunta de Galicia (Nos. GR 2007/085; IN607C 2016/03 and Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09) and the European Union (European Regional Development Fund-ERDF). G.F.C. thanks CNPq (grant 311963/2017-0) for the research fellowship. A.O.O. thanks CNPq for his PhD scholarship (grant 142339/2015-6). R.L.T.P thanks FAPESP (grant 2011/07623-8) and

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CAPES (Science without Borders program, number: 88881.068346/2014-01) for financial support.

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