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Molecular Recognition of Hydrophilic Molecules in Water by Combining the Hydrophobic Effect with Hydrogen Bonding Huan Yao, Hua Ke, Xiaobin Zhang, San-Jiang Pan, MingShuang Li, Liu-Pan Yang, Georg Schreckenbach, and Wei Jiang J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Sep 2018 Downloaded from http://pubs.acs.org on September 24, 2018

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Journal of the American Chemical Society

Molecular Recognition of Hydrophilic Molecules in Water by Combining the Hydrophobic Effect with Hydrogen Bonding Huan Yao,†,‡,¶ Hua Ke,†,¶ Xiaobin Zhang,ǁ,¶ San-Jiang Pan,† Ming-Shuang Li,† Liu-Pan Yang,† Georg Schreckenbach,ǁ and Wei Jiang†,* †

Department of Chemistry, Southern University of Science and Technology, Shenzhen, 518055, China School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China ǁ Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada ‡

ABSTRACT: During the last half a century, great achievements have been made in molecular recognition in parallel with the invention of numerous synthetic receptors. However, the selective recognition of hydrophilic molecules in water remains a generally accepted challenge in supramolecular chemistry but is commonplace in nature. In an earlier communication (J. Am. Chem. Soc. 2016, 138, 14550), we reported a pair of endo-functionalized molecular tubes that surprisingly prefer highly hydrophilic molecules over hydrophobic molecules of a similar size and shape. The hydrophobic effect and hydrogen bonding were proposed to be responsible, but their exact roles were not fully elucidated. In this article, we present a thorough study on the binding behavior of these molecular tubes towards 44 hydrophilic molecules in water. Principal component analysis reveals that the binding strength is weakly correlated to the hydrophobicity, volume, surface area, and dipole moment of guests. Furthermore, molecular dynamics simulations show the hydrophobic effect through releasing the poorly hydrogen-bonded cavity water contributes to the binding of all the hydrophilic molecules, while hydrogen bonding differentiates these molecules and is thus the key to achieve a high selectivity towards certain hydrophilic molecules over other molecules with a similar size and shape. Therefore, a good guest for these molecular tubes should meet the following criteria: the hydrogen-bonding sites should be complementary; the molecular volume should be large enough to expel all the cavity water but not too large to cause steric hindrance. This rule of thumb may also be used to design a selective receptor for certain hydrophilic molecules. Following these guidelines, a “best-fit” guest was found for the synconfigured molecular tube with a binding constant as high as 106 M-1.

1. INTRODUCTION

lar[n]arenes, 21 “Texas-sized box”, 22 bambus[n]uril, 23 cyanostar, corona[n]arene, 25 helic[n]arene, 26 biphen[n]arene, 27 oxatub[n]arene,28 and many others. Great achievements have been made, which lays the basis for their applications in selfassembly, interlocked structures, molecular machines, supramolecular catalysis, molecular sensors, and supramolecular materials.34 Nevertheless, water-soluble macrocycles are relatively rare.3,4,5 Most of the known water-soluble hosts are inefficient in the selective recognition of hydrophilic molecules in water. The known macrocyclic and self-assembled hosts can be roughly classified into two categories: the ones with hydrophobic cavities, such as cyclodextrins, and the ones with polar binding sites, such as crown ethers. Surprisingly, some of the hosts with only a hydrophobic cavity have been reported to be able to recognize hydrophilic molecules in water.11,12 Their binding selectivity heavily depends on the size and shape of guests, and rich information in the functional groups is largely ignored. Most importantly, the binding affinity to hydrophilic molecules is usually significantly weaker than that to the hydrophobic guests of similar size and shape. The hosts with polar binding sites can often bind polar molecules in nonpolar solvents, for example, through hydrogen bonding. However, the binding is significantly attenuated or even fully eliminated when transferred into water. The problem here is that the polar interactions, such as hydrogen bonding, are challenging to be exploited for molecular recognition in water.9e,37 The reasons are as follows: a) water competes with polar binding sites 24

Molecular recognition1 is the basis of life and the central topic of supramolecular chemistry. In particular, molecular recognition in aqueous solutions is attractive, since it may provide simplified models to understand complex biomolecular recognition and the promise for applications in biomedical and environmental sciences. The major tools for molecular recognition in water are water-soluble macrocyclic receptors,3,4,5 but water-soluble self-assembled hosts,6 foldamers,7 and tweezers are used as well. The recognition of cations, anions, and hydrophobic molecules/groups in water has been intensively studied. In contrast, the selective recognition of hydrophilic molecules in water remains a generally accepted challenge in the field of supramolecular chemistry and is thus substantially less explored. ,11,12 This class of molecules, including persistent environmental contaminants, drug molecules, and biomarkers for diseases, is very important. Hydrophilic molecules, usually containing several heteroatoms, are heavily solvated in water through the formation of intensive interactions with water molecules. It would cost high desolvation energy to recognize them. Since 1967, when Pedersen reported crown ethers,13 macrocyclic receptors have been the major tools in supramolecular chemistry. During the last five decades, numerous synthetic macrocyclic receptors have been reported and intensively investigated, including crown ethers, 15 cyclodextrins,4 calix[n]arenes, 16 cyclotriveradehydes, 17 calixpyrroles, 18 cucurbit[n]urils,5 “blue box”, 19 heterocalixaromatics, 20 pilACS Paragon Plus Environment 2

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of synthetic receptors, and b) water is very polar (1.85 D, ε = 78), which significantly weakens polar interactions in hostguest complexes. In contrast, hydrophilic molecules/groups can be well recognized by bioreceptors, even with high selectivity. Their binding pockets feature a deep hydrophobic cavity containing polar binding sites, such as hydrogen-bonding sites. In this way, hydrogen-bonding sites are shielded from bulk water, and the surroundings are relatively nonpolar. Together with the hydrophobic effect, hydrogen bonding can significantly enhance the binding affinity and selectivity. This is expressed in the binding pair of avidin and biotin (Figure 1a). The polar groups of biotin are complemented by the hydrogen-bonding sites in the cavity of avidin, and the residual hydrophobic groups are also satisfied in the deep hydrophobic cavity. Thus, a high binding affinity (1013 ~ 1015 M-1) is achieved, making this binding pair very popular in many applications. Analogously, natural lectins use a similar structural arrangement (many hydrogenbonding sites shielded inside a hydrophobic cavity) to achieve selective recognition of highly hydrophilic carbohydrates. However, water-soluble synthetic hosts having polar binding sites in a hydrophobic cavity are very rare41,42 and difficult to synthesize. By mimicking the binding pockets of bioreceptors, we proposed endo-functionalized molecular tubes to meet this criterion (Figure 1a): positioning hydrogen-bonding donors inside a deep tubular cavity. In an earlier attempt, a pair of water-soluble endo-functionalized molecular tubes (1a and 1b, Figure 1b), which was first reported by Glass and coworkers for the recognition of lipid molecules in water through the hydrophobic effect, have been used to achieve the selective recognition of a series of highly hydrophilic molecules in water,47,48, including a Group 2B carcinogen and persistent environmental contaminant -- 1,4-dioxane. The binding behavior of these endo-functionalized molecular tubes is drastically different from that of other macrocyclic and self-assembled hosts. For example, the binding affinity to 1,4-dioxane was significantly increased when transferring the compounds from chloroform (10 ~ 102 M-1) to water (103 ~ 104 M-1); a very high selectivity was achieved for the highly hydrophilic molecule 1,4-dioxane over other more hydrophobic molecules with a similar size and shape, such as 1,3-dioxane and tetrahydropyran.47

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39

40

43

44

45

46

49

Figure 1. a) Bioinspired design of endo-functionalized molecular tubes. b) Chemical structures of the molecular tubes.

This earlier research, reported as a communication, leaves several unanswered questions. We proposed that the hydrophobic effect and hydrogen bonding are responsible for the high binding affinity and high selectivity towards the highly hydrophilic molecule 1,4-dioxane. However, what are their exact roles? In the literature, quite weak C-H⋅⋅⋅π interactions have been suggested to be responsible for the binding of hydrophilic molecules in water.11b,11d Is this reasonable? Even with molecular tubes 1a and 1b, is hydrogen bonding the major contributor for the binding of all the hydrophilic molecules? What is the role of hydrogen bonding, especially in the high binding selectivity among molecules of similar size and shape? How can the hydrophobic effect contribute to the binding of hydrophilic molecules? The release of the cavity water has been proposed to be responsible for this. However, evidence for the state of the cavity water is needed. Can we achieve a stronger binding (Ka > 105 M-1) with these molecular tubes? Moreover, the binding pockets of these endo-functionalized molecular tubes closely resemble the protein binding pockets. Further in-depth research will not only provide general guide-

Figure 2. Chemical structures of the small molecules involved in this research as guests. Guest names or abbreviations used in other places can be found here.

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lines for the design of efficient receptors for biologically and Table 1. Summary of molecular descriptors and binding constants (Ka) of the guests with 1a and 1b in water at 25 °C. guest ethanol isopropanol

V (Å3)a

ΩAa

S (Å2)a

SMAX (M)b

logPb

µ (D)c

α (Bohr3)c

Ka (1a, M-1)

Ka (1b, M-1)

76.54

0.11373

93.94

misc.d

-0.30

1.88

25.95

9 ± 2h

43 ± 13h

h

100.13

0.03907

113.95

acetonee

91.26

0.05329

diethy ether

123.58

0.17298

DEAf

129.91

20 ± 5h

misc.

0.05

1.89

36.36

107.99

misc.

-0.24

3.09

33.22

100 ± 10

110 ± 10

139.41

8.15 × 10-1

0.89

1.38

48.28

290 ± 39h

330 ± 88h

0.17562

142.89

misc.

0.58

0.48

50.89

1500 ± 120i

460 ± 11i

68.73

0.20998

85.62

misc.

-0.34

3.88

22.47

8 ± 3h

160 ± 43h

102.16

0.03143

116.48

misc.

-1.35

4.92

44.68

31 ± 4

130 ± 10

DMF

105.78

0.08156

121.33

misc.

-1.01

4.44

40.52

310 ± 31

120 ± 12

N-ethylacetamide

130.92

0.13133

144.55

1.32g

-0.19g

4.10

50.95

65 ± 10h

150 ± 25h

nitromethane

74.53

0.05675

91.54

1.82

-0.33

3.85

24.39

17 ± 8h

110 ± 2h

DCE

107.87

0.21466

121.44

8.61 × 10-2

1.48

0.00

40.64

270 ± 23j

-1

acetonitrile e

DMSO e

dimethoxymethane

113.25

0.08744

445.61

3.02 × 10

0.00

2.38

40.67

2,2-dimethoxypropane

152.34

0.02584

157.50

7.22 × 10-2

1.38

2.30

140.88

-1

0.73

-1g

g

EA

125.99

DMC oxetane

e

0.12646

114.94

0.13347

128.20

9±4

400 ± 21j

60.81

6700 ± 140 49 ± 13h

5200 ± 590i 140 ± 3h

1.94

47.95

3400 ± 24i

2300 ± 140i

0.07

0.11

40.37

misc.

-0.14

2.50

9.08 × 10 9.44 × 10

i

i

32.72

2300 ± 110 300 ± 30

1400 ± 52i 240 ± 25

88.20

0.04207

102.57

e

THF

107.45

0.04022

119.52

misc.

0.46

2.26

43.16

230 ± 25

90 ± 10

THPe

127.01

0.04092

135.38

9.31 × 10-1

0.82

1.83

53.97

68 ± 7

60 ± 6

151.49

-2

1.92

1.70

64.13

380 ± 40

150 ± 20

oxepane

e

148.63

cyclohexanone

140.93

0.03939 0.06941

147.72

2.68 × 10

-1

2.34 × 10

0.81

3.42

61.31

6 ± 1h

h

35 ± 5

thiane

140.33

0.04774

146.85

1.27 × 10

2.28

2.37

65.96

65 ± 6

120 ± 9h

1,3-dioxolane

96.85

0.04306

109.98

3.74

-0.37

1.48

36.21

430 ± 39i

260 ± 5i

MDO

117.76

0.06975

131.51

7.94 × 10-1g

0.08g

1.35

46.61

22000 ± 730i

8100 ± 79i

propylene carbonate

119.00

0.06329

133.46

1.71

-0.41

6.16

47.59

1,3-dioxanee

115.90

0.04233

126.15

9.94 × 10-1

0.18

1.44

46.19

1,4-dioxene

106.94

0.04980

120.68

misc.g

-0.39g

0.95

43.75

116.07

0.04253

126.70

misc.

-0.27

0.00

124.32

0.04235

130.78

misc.

-0.86

2.01

130.42

0.04224

134.82

misc.

-1.50

0.00

54.09

104.50

0.04396

116.30

1.94

1,4-dioxane

e

morpholinef piperazine

f

s-trioxane furan pyrrole

93.86 97.36

0.06254 0.06252

105.94 110.46

-2

h

i

51 ± 5 210 ± 21

62 ± 5i 210 ± 21

47.23

1800 ± 73i 14000 ± 1500

1000 ± 76i 3200 ± 300

50.72

190 ± 8i

130 ± 6i i

40 ± 3i 17 ± 8h

-0.43

2.65

38.87

210 ± 17 47 ± 3h

-1

1.34

1.08

36.05

490 ± 23i

-1

0.75

1.90

39.68

1500 ± 59

390 ± 2i

-2

4000 ± 230i

2100 ± 200i

1.47 × 10 7.01 × 10

150 ± 20i i

thiophene

107.02

0.06994

117.95

3.59 × 10

1.81

1.02

49.12

oxazole

85.54

0.06260

100.66

1.55

0.12

1.53

32.51

130 ± 22

thiazole

101.76

0.07153

113.00

6.32 × 10-1

0.44

1.32

45.91

imidazole

91.92

0.06258

105.26

2.34

-0.08

3.97

36.16

1400 ± 220i 330 ± 33h

420 ± 14i 69 ± 13h

pyrazole

91.76

0.06252

105.34

1.20

0.26

2.47

36.10

180 ± 9i

130 ± 14i

1,2,4-triazole

85.74

0.06259

100.03

6.14

-0.58

2.99

32.49

61 ± 14i 2100 ± 350j 220 ± 29i

i

tetrazole

83.11

0.06255

95.43

3.08 × 10

-0.60

5.77

29.72

210 ± 21i 1800 ± 650j

pyridine

111.97

0.06257

122.09

misc.

0.65

2.48

49.41

590 ± 48i

pyrimidine

105.06

0.06255

117.14

3.58

-0.40

2.61

45.33

62 ± 5

pyrazine

104.15

0.06280

117.32

2.72

benzene toluene

116.30 141.22

0.06250 0.08711

126.89 147.37

-1

i

-0.26

0.00

45.97

2200 ± 38i

-2

2.13

0.00

53.33

1300 ± 193i

-3

2.73

0.36

65.49

2.29 × 10 5.71 × 10


130 ± 10i

18 ± 4i 1900 ± 100i 750 ± 69i i

9500 ± 1700

9900 ± 1400i


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a

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Details of how the volume (V), asphericity (ΩA), and surface area (S) were calculated are given in the supporting information. b Maximum solubilities in water (SMAX) and values of the logarithm of the octanol:water partition coefficient (logP) were taken from ref 50. c Values were calculated using Gaussian 03 at the RB3LYP/6-31G level of theory. d Miscible with water. e The binding constants of these guests as determined by NMR titrations have been reported earlier.47 f The binding constants of these guests were determined in the phosphate buffer (pH = 12). g Values were taken from ref 51. h The binding constants of these guests were determined by NMR titrations and are listed in Table S3. i The binding constants of these guests were determined by fluorescence titrations and are listed in Table S2. j The binding constants of these guests were determined by ITC titrations and are listed in Table S4. All the titration experiments were repeated thrice, and the averaged values with standard deviations are reported here.

environmentally relevant hydrophilic molecules but also help in understanding molecular recognition in complex biological systems. In this research, we would like to answer the abovementioned questions by studying in detail the binding behaviors of the molecular tubes towards 44 small hydrophilic molecules in water. Principal component analysis (PCA) was employed to reveal the factors that affect the binding strength of hydrophilic molecules. The roles of the hydrophobic effect and hydrogen bonding were analyzed, and general guidelines for selectively recognizing hydrophilic molecules in water were obtained. These were further used to find a “best-fit” guest which can tightly bind these molecular tubes.

2. RESULTS AND DISCUSSION Determination of Binding Constants and Thermodynamic Parameters. The binding targets of this research are focused on neutral hydrophilic molecules. To meet this criterion, 44 guests containing minimal hydrophobic groups were selected (Figure 2). Their solubility data in water can be found in Table 1. Most of them are highly hydrophilic: 14 guests are miscible with water, and 23 guests have a solubility in water of over 0.1 M. These guests can be divided into four classes: a) linear/acyclic molecules, b) nonaromatic heterocycles, c) aromatic heterocycles, and d) aromatic hydrocarbons. The heteroatoms were focused on N, O, and S to emphasize the role

of hydrogen bonding, but 1,2-dichloroethane, benzene, and toluene were also used as guests. All these guests undergo upfield chemical shifts in the 1H NMR spectra of their 1:1 mixtures with 1a/1b (Figures S1S72), suggesting they are inside the cavities of the molecular tubes and experience the shielding effect of the four naphthalenes. Their binding constants were further determined. To be consistent with the earlier research,47 the binding constants and thermodynamic parameters for most of the guests were determined in deionized H2O or D2O. The pH values of the solutions containing 1a and 1b (0.5 mM) are 7.83 and 7.88, respectively. This suggests that most of the guests exist in the neutral form in these solutions (for the pKas of some basic guests, see Table S1). However, the pKas of guests DEA, morpholine, and piperazine are 10.84, 8.50, and 9.73, respectively. To avoid protonating these guests, their binding constants were determined in a phosphate buffer (pH = 12.0). The binding data are listed in Tables 1 and S2-S4. Most of the guests induce a fluorescence enhancement of the hosts. Therefore, fluorescence titrations (FL, Figures S73-S122) were used to determine their binding constants. For the guests that do not induce a fluorescence response, NMR titrations (Figures S130-S185) were performed to afford the binding constants. The binding constants of guests DCE and tetrazoles were obtained by isothermal titration calorimetry (ITC). Of all these guests, only 18 guests’ thermodynamic parameters (Ka, ∆G°,

Figure 3. PCA biplot diagram obtained by analyzing eight variables (logKa(1a), logKa(1b), V, S, α, ΩA, µ, and logP) for each guest. Both loadings (blue lines) and scores (red solid circles) are represented.


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∆H°, and ∆S°) can be determined by ITC titrations. For the case that the binding constant is smaller than 103 M-1 and the guests are highly soluble in water, the ITC titration method for low affinity binding introduced by Turnbull and Daranas was adopted. A 1:1 binding stoichiometry was assumed for all the guests, which is supported by great non-linear fittings and Job’s plots of the molecular tubes with the very small guests: acetonitrile, ethyl ether, and ethyl acetate (Figures S123-129). All the titration experiments were repeated three times. The binding constants from different methods are consistent with each other. The binding data for guests 1,4-dioxane, 1,3dioxane, DMF, DMSO, acetone, THF, THP, oxetane, and oxepane, as determined by fluorescence, NMR, or ITC titrations, have been reported earlier47 but were included here for comparison. Principal Component Analysis (PCA). Most of the binding constants are within the range between 10 and 104 M-1. This is very decent when one considers most of these molecules are highly hydrophilic and not usually chosen as guests for molecular recognition. Only three guests (MDO, 1,4dioxane, and toluene) show binding constants above or close to 104 M-1. Eleven guests (DEA, dimethoxymethane, EA, DMC, 1,4-dioxene, pyrrole, thiophene, thiazole, tetrazole, pyrazine, and benzene) have binding constants in the range of 103 to 104 M-1. All the other binding constants are below 102 M-1. This suggests that a high binding selectivity exists. To reveal the guest parameters that affect the binding strength, PCA was performed to elucidate the correlations of the logarithm of the binding constants (logKa) with six molecular descriptors: the logarithm of the octanol : water partition coefficient (logP), dipole moment (µ), molecular volume (V), surface area (S), polarizability (α), and asphericity (ΩA). PCA provides a graphic representation of the correlations that exist in the data set. This method has been widely applied in analyzing chemical sensor array data.53 When the correlation coefficient (r) between two parameters is close to 1 or -1, a strong correlation exists, but the two parameters make a positive or negative contribution to each other. PCA has recently been used by Nitschke et al.12 to elucidate the factors governing guest binding strength in the hydrophobic cavity of a selfassembled host. They revealed that logKa is highly correlated to µ and logP. Lower µ and higher logP values lead to higher binding affinities. That is, hydrophobic guests show stronger binding than do hydrophilic molecules. Volume also affects the binding affinities but to a less extent. As shown in Figure 3, the result of the PCA performed on the data (eight variables: logKa(1a), logKa(1b), V, S, α, ΩA, µ, and logP) in Table 1 was drawn as a biplot diagram in which eight-dimensional space was reduced to a two-dimensional space with two principal components. The values of both the variables (loadings, blue lines) and the components (scores, red solid circles) for each guest are reported in the diagram, and the correlation coefficients are listed in Table S5. An overview regarding how these guest parameters affect the binding affinities may be obtained by closely examining this biplot diagram. The binding constants of 1a and 1b are highly correlated with each other (r = 0.862), suggesting the two cavities are rather similar in binding properties. Therefore, the binding data of 1a are mainly used in the following analysis. Generally, there is no strong correlation between the binding constants and these six molecular descriptors (V, S, α, ΩA, µ, and logP). This may be due to the high complexity of this binding system, 52

53

and a single parameter is not sufficient to significantly affect the binding. However, weak correlations do exist: hydrophobicity (logP, r = 0.250 for 1a), volume (V, r = 0.221 for 1a), surface area (S, r = 0.297 for 1a), and polarizability (α, r = 0.225 for 1a) make positive contributions to the strength of guest binding; the dipole moment (r = -0.476 for 1a) makes a negative contribution, while asphericity (ΩA, r = 0.023 for 1a) is more or less irrelevant. The general trend is similar to that for the self-assembled host reported by Nitschke et al.12 This indicates these endo-functionalized molecular tubes prefer guests that have a large volume, large surface area, high hydrophobicity, and low dipole moment. Examples can be found by closely looking at the score plot in Figure 3 and the data in Table 1. 13 of the abovementioned 14 guests with binding constants above 103 M-1 for 1a have smaller dipole moments than that of the other guests. The exception is tetrazole, for which the reason is still unknown. Additional hydrophobic groups usually lead to an increase in binding affinity, for example, 1,3-dioxolane (430 M-1 for 1a) vs. MDO (22000 M-1 for 1a), benzene (1300 M-1 for 1a) vs. toluene (9500 M-1 for 1a), and methanol (negligible for 1a, Figure S1) vs. ethanol (9 M-1 for 1a). However, the prerequisite is that the guest cannot be too large; otherwise, the binding affinity will be significantly attenuated due to an incongruent fit with the cavity space, for example, dimethoxymethane (6700 M-1 for 1a) vs. 2,2-dimethoxypropane (49 M-1 for 1a). This analysis provides a general picture of the binding ability of these molecular tubes: the molecular tubes prefer to bind hydrophobic molecules with the appropriate size and shape. However, one should note that this rule is only valid among similar hydrophilic guests. The hydrogen-bonding ability was not included in these molecular descriptors. This rule cannot fully explain the binding behaviors of the molecular tubes which in many cases prefer hydrophilic molecules instead of the hydrophobic molecules with similar size and shape, for example, 1,4-dioxane (14000 M-1 for 1a) vs. tetrahydropyran (68 M-1 for 1a), dimethoxymethane (6700 M-1 for 1a) vs. diethyl ether (290 M-1 for 1a), and pyrazine (2200 M-1 for 1a) vs. pyridine (590 M-1 for 1a). The dipole moment alone could not account for these drastic changes in binding strength. Therefore, further in-depth analyses and more control experiments are needed to paint a complete picture. The Role of the Cavity Water. The driving forces for the binding of hydrophilic molecules in several hosts with only a hydrophobic cavity11,12 were partly attributed to weak noncovalent interactions, such as C-H⋅⋅⋅π interactions. Is this reasonable? If yes, then why do our molecular tubes47 show an increased binding affinity to 1,4-dioxane when transferred from chloroform to water? Water is more polar than chloroform, and weaker interactions should be observed in water. If no, what is then the driving force? Further research is needed to answer this question. To confirm and test whether enhanced binding is limited to 1,4-dioxane, the binding constants of molecular tubes 2a and 2b with six representative guests (EA, DMC, benzene, MDO, 1,4-dioxane, and pyrazine) in CDCl3 were determined through NMR titrations (Figures S203-S220). All these guests have binding constants above 103 M-1 with these molecular tubes in water. However, their binding constants are substantially weaker in CDCl3. EA, DMC, and benzene show no detectable binding in CDCl3. While the binding constants of MDO, 1,4dioxane, and pyrazine decreased by ca. two orders of magnitude from water to chloroform (for 2a: MDO, 41 ± 1 M-1; 1,4-


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Table 2. Parameters of the cavity water of 1a and 1b obtained from molecular dynamics simulation.a 1a N

b

c

m

1b d

PC

b

N

mc

hydrophobic region

1.5

1.67

2.3e

2.30

hydrogenbonding region

3.0

3.20 (2.80)f

1.5e

2.83 (1.77)f

whole cavity

4.5

2.76

3.8

2.67

48%

PCd

35%

a

Only the results with the tip4pEW water model were shown here. For the results with the tip3p water model and the computational details, please see the supporting information. The average number of hydrogen bonds per H2O in bulk water is 3.62,54a b average number of the water molecules in this region or cavity; c average number of hydrogen bonds per H2O in this region or cavity (hydrogen bonds were considered if D-H⋅⋅⋅A ≤ 130° and D−A ≤ 3.5 Å), and d packing coefficient; e this was obtained by summing up or averaging the numbers from two hydrophobic regions in 1b. f The average number of hydrogen bonds excluding N-H⋅⋅⋅O hydrogen bonds is given in brackets.

dioxane, 62 ± 1 M-1; pyrazine, 11 ± 1 M-1; for 2b: MDO, 48 ± 3 M-1; 1,4-dioxane, 98 ± 5 M-1; and pyrazine, 13 ± 1 M-1). This result is surprising because synthetic hosts with hydrogenbonding sites and an ill-defined cavity show decreased binding affinities to hydrophilic molecules when transferred from nonpolar solvents to water.36 This suggests that water and thus the hydrophobic effect are very important even for the binding of hydrophilic molecules in water by these molecular tubes. How can the hydrophobic effect be important for recognizing hydrophilic molecules in water? We proposed earlier that the cavity water molecules are less hydrogen-bonded than the bulk water.47 The release of these water molecules upon complexation is energetically favorable and thus responsible for the binding of hydrophilic molecules in a hydrophobic cavity. However, no evidence was provided in this earlier research. Herein, molecular dynamics (MD) simulations were performed to reveal the state of water molecules inside the cavities of 1a and 1b.54a The computed parameters are listed in Tables 2 and S9-S12, and representative snapshots are shown in Figure 4a. The average number of hydrogen bonds per water molecule in the whole cavity (2.76 for 1a and 2.67 for 1b) is markedly less than that of the bulk water (3.62).54a Therefore, the cavity water molecules are indeed poorly hydrogen-bonded. 1a contains ca. 4.5 water molecules in its cavity, while 1b has ca. 3.8 water molecules. Once these cavity water molecules release to the bulk, more hydrogen bonds should be formed. Therefore, upon complexation, the release of these poorly hydrogenbonded cavity water should be one major driving force for the binding of hydrophilic molecules. This explains why higher binding constants were achieved in water than in chloroform and why hydrophilic molecules can be bound inside a hydrophobic cavity.10,11 The cavities of 1a and 1b can be further divided into hydrogen-bonding regions (where the amide protons are located) and hydrophobic regions (Figure 4b and Figure S221). On average, each encapsulated water molecule in the hydrogenbonding regions forms more hydrogen bonds than that in the hydrophobic regions. This is due to the contribution of the inward-directed amide protons. Glass et al. also reported an54

Figure 6. Changes of the chemical shift of the amide protons of 1a (1.0 mM, H2O/D2O = 9:1) with the addition of guests EA, DMC, benzene, DMO, 1,4-dioxane, or pyrazine. Figure 4. a) Representative MD snapshots of 1a and 1b in water. Green dotted lines indicate the hydrogen bonds involving the encapsulated water molecules. b) Hydrophobic and hydrogenbonding regions of 1a.

other pair of molecular tubes by substituting the amide groups in 1a and 1b with allyl groups. These new molecular tubes have substantially stronger binding affinities (by two orders of magnitude) towards the hydrophobic tails of lipids than do the amide counterparts 1a and 1b. Replacing the inward-directed amide groups makes the encapsulated water even poorer in hydrogen bonding. Thus, the release of these cavity water is even more energetically favorable. This may explain the increased binding affinities. In another word, introducing polar binding sites into a hydrophobic cavity decreases its hydrophobicity and thus its binding strength to hydrophobic molecules/groups. However, it is favorable for the binding of hydrophilic molecules with complementary hydrogen-bonding sites. This may contribute to the reversed binding preference of hydrophilic molecules over hydrophobic molecules (see below). Water molecules in the cavity of 1b have a packing coefficient of 38% in contrast to the 48% for 1a, which are however less than the value of the bulk water (63%). The cavity of 1a is more well-defined and contains more poorly hydrogenbonded cavity water molecules than 1b does. These may explain why 1a is generally a better binder than 1b and why the best binding until now was achieved with 1a rather than 1b (MDO, 22000 M-1 (1a) vs. 8100 M-1 (1b) and 1,4-dioxane, 14000 M-1 (1a) vs. 3200 M-1 (1b)). This suggests that the size and shape of the hydrophobic cavity also play an important role in the binding affinity. The Role of Hydrogen Bonding. It was shown in Nitschke’s self-assembled cage with a hydrophobic cavity that hydrophobic guests are preferred over hydrophilic guests.12 For example, tetrahydropyran (740 M-1) is a better guest than 1,3dioxane (330 M-1) and 1,4-dioxane (150 M-1). However, we reported earlier that 1,4-dioxane (14000 M-1) is a significantly better guest for 1a than are 1,3-dioxane (210 M-1) and tetrahydropyran (68 M-1).47 At first glance, the reversed binding selectivity was surprising and puzzling. Compared to the hosts with only a hydrophobic cavity, these molecular tubes have additional hydrogen-bonding sites in their hydrophobic cavity. 55

56


6

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Figure 5. Single-crystal X-ray structures of the complexes of (a) 2a or (b) 2b with the guests. CCDC numbers for these crystals: 18211961821200, 1821203-1821212.

We therefore proposed earlier47 that hydrogen bonding should be responsible for this surprising behavior and the high selectivity to the highly hydrophilic molecule 1,4-dioxane. However, is hydrogen bonding significantly involved in the binding of all the other hydrophilic molecules? These hydrogen bonds are shielded in a hydrophobic cavity and not interfered with the bulk water molecules. Therefore, crystal structures may help reveal the role of hydrogen bonding in the binding of all these hydrophilic molecules. The slow evaporation of the CH2Cl2 solutions of 2a or 2b in the presence of guests affords single crystals of the complexes, which are suitable for X-ray crystallography. The single-crystal structures are shown in Figure 5. None of these crystals were grown from water, but the binding mode of guests in the host cavity should be similar to that in water since most of the solvent molecules in the cavity are anyway expelled upon guest encapsulation. Single hydrogen bond (for guests EA, DEA, and Nethylacetamide) or N-H⋅⋅⋅π interactions (for guests DMF, pyrrole, thiazole, imidazole, and benzene) were detected in most of these crystal structures. These guests usually show decent binding affinities (102 ~ 103 M-1 for most of them) with 1a or 1b in water. It is noted that some of these guests contain hydrogen-bonding acceptors, but no hydrogen bonds are formed. This may be due to steric reasons. For example, weak N-H⋅⋅⋅π interactions between DMF’s π system and the host’s amide proton exist instead of a N-H⋅⋅⋅O hydrogen bond. This may be because forming a hydrogen bond with the carbonyl oxygen atom of DMF would render the large methyl groups too close

to the other amide proton of the host and cause steric repulsion. While for N-ethylacetamide, the host’s NH proton is hydrogen bonded to the guest’s carbonyl oxygen atom, but the steric repulsion between the two amide protons from the host and the guest makes the guest’s amide bond twisted in a nonplanar form. This is quite unusual for an amide bond. Two short and assumably strong hydrogen bonds were de-

Figure 6. Changes of the chemical shift of the amide protons of 1a (1.0 mM, H2O/D2O = 9:1) with the addition of guests EA, DMC, benzene, DMO, 1,4-dioxane, or pyrazine.


7


Page 8 of 12

Table 3. ∆G°, ∆H° and -T∆S° (kJ mol ) of the complexes of 1a (left) and 1b (right) with the six representative guests. The data were determined by ITC titrations in D2O or H2O. -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

1a ∆G° EA DMC benzene MDO

Figure 7. Thermodynamic data (∆H° and T∆S°) for the binding of neutral guests with 1a (red dots) or 1b (blue triangles).

1,4-dioxane pyrazine

tected for guests 1,4-dioxane,47 pyrazine, MDO, DMC, and dimethoxymethane. The two hydrogen-bonding donors in the cavities of the molecular tubes are both satisfied. All these guests have binding constants above 103 M-1. These perfectly matched hydrogen bonds should be responsible for the high binding affinities as well as the high selectivity over the molecules with a similar size and shape but incongruent hydrogenbonding acceptors. In the absence of guests, the cavity water molecules also form hydrogen bonds with the amide protons in the cavities of 1a and 1b. This is supported by MD simulations (Figure 4a). Binding to a guest would replace these water molecules and destroy these hydrogen bonds. However, new hydrogen bonds with guest molecules will form. Either stronger or weaker hydrogen bonds are formed when replacing the cavity water molecules with a guest. Therefore, this situation must be considered when one evaluates the contribution of hydrogen bonding to the guest binding. NMR titrations of molecular tube 1a in H2O : D2O (9:1) by six representative guests (EA, DMC, benzene, MDO, 1,4-dioxane, and pyrazine) were performed (Figures S223-S228) to reveal this effect. Since H2O is dominant in this solution, the amide protons are not fully exchanged with deuterium and thus visible in NMR spectra. The chemical shifts of the amide protons can be used as an estimate of the changes in the strength of these hydrogen bonds. Stronger hydrogen bonds would cause a downfield shift of these proton signals, while an upfield shift suggests the formation of weaker hydrogen bonds. As shown in Figure 6, the amide protons shift downfield with the addition of MDO, 1,4-dioxane, or pyrazine, suggesting the formation of stronger hydrogen bonds than those with the encapsulated water molecules. However, with guests EA, DMC, or benzene, the amide protons shift upfield, indicating the formation of weaker hydrogen bonds with these guests. That is, from the point of view of hydrogen bonding, the binding is favorable for guests MDO, 1,4-dioxane, and pyrazine but unfavorable for guests EA, DMC, and benzene. This is in line with the binding studies in CDCl3. Considering the high desolvation penalty of EA and DMC, the binding is even more unfavorable. Consequently, the binding to EA and DMC should mainly come from the hydrophobic effect, that is, the release of the cavity water. While for guests MDO, 1,4dioxane, and pyrazine, hydrogen bonding and the hydrophobic 57

58

1b

∆H° -T∆S°

∆G°

ΔH° -TΔS°

H2 O

-20.2

-21.6

1.4

-18.9

-26.1

7.2

D2 O

-21.2

-20.5

-0.7

-19.9

-23.3

3.4

H2 O

-18.7

-24.0

5.3

-17.8

-23.9

6.1

D2 O

-19.5

-21.7

2.2

-18.6

-20.0

1.4

H2 O

-17.7

-12.2

-5.5

-17.1

-10.1

-7.0

D2 O

-18.6

-7.5

-11.1

-17.3

-10.2

-7.1

H2 O

-24.3

-25.0

0.7

-21.9

-23.8

1.9

D2 O

-25.0

-25.5

0.5

-22.8

-24.1

1.3

H2 O

-23.5

-25.6

2.1

-20.6

-25.5

4.9

D2 O

-24.1

-26.5

2.4

-21.7

-26.2

4.5

H2 O

-19.8

-19.9

0.1

-18.4

-18.1

-0.3

D2 O

-20.2

-20.4

0.2

-18.7

-21.1

2.4

effect through releasing the cavity water both contribute significantly. This explains why a high binding selectivity was achieved for these guests over that of the other guests with similar size and shape. This is consistent with the statement by Biedermann et al. on how to design a high-affinity receptor with high selectivity. To summarize the findings discussed in the above three sections, we conclude a good guest for these endo-functionalized molecular tubes should meet the following criteria: a) the guest should contain two hydrogen-bonding acceptor atoms that are located in the appropriate orientation and distance to complement the hydrogen-bonding donors in the cavities. An additional heteroatom is better eliminated to minimize the dipole moment; b) when the hydrogen-bonding sites are satisfied, a large hydrophobic group is needed to expel all the cavity water and to maximize the contribution of hydrophobic effect, but the hydrophobic group should not cause any steric repulsion with the cavity walls. Thermodynamic Consequence. How would this unique combination of hydrogen-bonding sites with a hydrophobic cavity affect the binding thermodynamics? The thermodynamic parameters (∆G°, ∆H°, and ∆S°) for 18 guests were available from ITC titrations (Figure 7, and Table S4). For most of the guests, the binding is generally dominated by the enthalpic contribution with a slightly favorable or unfavorable entropic contribution. However, for benzene and toluene, both enthalpy and entropy are favorable. The cavity water molecules are less hydrogen-bonded than the bulk water molecules. Upon release into the bulk, more hydrogen bonds should be formed. This was suggested to be the cause of the dominated enthalpy in the guest binding of a well-defined hydrophobic cavity.54a Nevertheless, a more complex mechanism is also possible.43 Weak enthalpy-entropy compensation (Figure 7) is observed for the binding data of both 1a and 1b. These data are more scattered than those of other synthetic systems. With respect to the cause, not only the tightness of the binding should be considered but also the entropy of solvation may change. The release of cavity water from the hosts and the desolvation of hydrophilic guests could further complicate the situation. For different hydrophilic guest molecules, their solvation and desolvation are different, which is rather distinct


59

60

8

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from hydrophobic molecules. Together, this may explain why the enthalpy-entropy compensation is weak here. In addition, the strong enthalpy-entropy compensation in other supramolecular systems was suggested to be possibly due to large uncertainties in the enthalpy measurement.61 That is, a weak enthalpy-entropy compensation should be more common. A clear solvent isotope effect was also observed. ITC titrations of 1a and 1b by the six representative guests (EA, DMC, benzene, MDO, 1,4-dioxane, and pyrazine) in both H2O and D2O were performed (Tables 3 and S13, and Figures S229S252). Generally, solvent isotope effects (KD/KH = 1.1 ~ 1.5, ∆∆GD/H = -0.2 to -1.0 kJ/mol) were observed for all the cases. However, for the guests (EA, DMC, and benzene) that form weaker hydrogen bonds than those of the encapsulated water molecules, the binding is less exothermic in D2O than in H2O (∆∆HD/H = 0 ~ 4.7 kJ/mol), and a large enthalpy-entropy compensation was seen, while for the guests forming stronger hydrogen bonds, the opposite was observed (∆∆HD/H = -3.0 to 0.3 kJ/mol), and the magnitude of enthalpy and entropy changes is substantially smaller. The solvent isotope effect for these molecular tubes is larger when compared to that of cyclodextrins (KD/KH ≤ 1.25) 62 and smaller when compared to that of cucurbiturils (KD/KH ≥ 1.5).59 Although the same cavities are involved, and similar cavity water molecules are released, the hydrogen-bonding strength among the cavity water is different in D2O and H2O. It is wellknown that the zero-point vibrational energy of the O−D bonds of D2O is lower than for the O−H bonds of H2O. Therefore, D2O forms stronger hydrogen bonds than does H2O.63 In addition, the amide protons in the host cavities are labile and would be fully exchanged to deuterium in D2O. The hydrogen bonds between host and guest would also be influenced through the H/D exchange of the amide protons. All these factors together contribute to the observed solvent isotope effect and explain the different thermodynamic origins of the two groups of guests. The “Best-Fit” Guest. Following the criteria for the binding with these molecular tubes, a “best-fit” guest was searched for. From the crystal structures (Figure 4), these hydrophilic guests only occupy the hydrogen-bonding region and part of the hydrophobic region of the cavity. Additional water may coexist with these guest molecules in the cavity.49 Therefore, a higher binding affinity may be achieved with a guest to fully occupy the cavity space and thus expel all the cavity water and to simultaneously satisfy the hydrogen-bonding sites.48 1,4Dioxane and MDO with complementary hydrogen-bonding sites are the only two guests whose binding constants are larger than 104 M-1 (with 1a). Therefore, these two guests were used as the structural basis to search for the “best-fit” guest. Since the unfilled region is hydrophobic, the fusion of a hydrophobic group to these guests was attempted to improve the binding affinities. Thus, guests 3 and 4 (Table 4) were selected, and their binding constants were determined (Figures S253S262 and Table 4). However, guest 3 does not give a significantly higher binding affinity, presumably due to steric hindrance with the cavity walls. In contrast, guest 4 achieved a binding constant of 106 M-1 with 1a, which is better than that of the epoxide 2-methyl-3-phenyloxirane (105 M-1) reported earlier.48 This binding constant is rather high when one considers that the guest is small and contains a hydrophilic acetal group. The binding is again mainly contributed by enthalpy with an unfavorable entropy. Guest 4 not only satisfies the hydrogen-bonding sites in the cavity of 1a but also structurally complements the hydrophobic region and expels all the cavity

Table 4. Association constants Ka ( M ) and thermodynamic parameters (∆G°, ∆H° and -T∆S°; kJ mol ) of molecular tubes 1a and 1b with 3 and 4 in H2O at 25 °C as determined by fluorescence (FL) and ITC titrations -1

-1

FL Ka×10 3

4

ITC 4

Ka×10

4

∆G°

∆H°

-T∆S°

1a

1.6 ± 0.3

1.1 ± 0.1

-23.1

-38.8

15.7

1b

2.9 ± 0.1

1.3 ± 0.1

-23.5

-38.7

15.2

1a

220 ± 18

140 ± 0.1

-35.2

-45.1

9.9

1b

51 ± 0.1

46 ± 2.7

-32.4

-52.7

20.3

water molecules. From another point of view, guest 4 can be considered to be obtained by attaching additional polar acetal group to benzene. Competition experiments (Figure S263) between 4 and benzene (Ka = 1300 M-1, for 1a) in the presence of 1a indicate that 1a overwhelmingly prefers guest 4 over benzene. This suggests that the additional polar acetal group is crucial for the high binding affinity of 4. In addition, this indicates that these endo-functionalized molecular tubes are also good receptors for molecules with both hydrophilic and hydrophobic groups, which is the common structural feature for the majority of organic molecules. This also suggests strong binding for synthetic receptors is not limited to highly hydrophobic guests,3b and a well-solubilized molecule may also provide nanomolar binding provided a synthetic host with complementary cavity size and inwarddirected binding sites is available.

3. CONCLUSIONS In this article, we reported a systematic study on the binding behavior of the endo-functionalized molecular tubes to 44 hydrophilic molecules in water by using NMR, fluorescence, and ITC titrations, X-ray crystallography, and molecular dynamics simulations. Principal component analysis reveals that the binding strength is weakly correlated to the hydrophobicity, volume, surface area, and dipole moment of guests. Furthermore, the hydrophobic effect through the release of the poorly hydrogen-bonded water molecules in a well-defined cavity is the major driving force. Hydrogen bonding is the key factor in determining the high binding selectivity to certain hydrophilic molecules over other molecules with similar size and shape: a) introducing hydrogen-bonding sites make the cavity less hydrophobic and thus decreases the binding affinity towards hydrophobic guests with similar size and shape; b) among hydrophilic molecules, only the ones with complementary hydrogen-bonding sites form stronger hydrogen bonds than does the encapsulated water. Therefore, weak noncovalent interactions, such as C-H⋅⋅⋅π interactions, should not contribute much to the binding of hydrophilic molecules in water. These findings clarify the role of the hydrophobic effect and noncovalent interactions in the binding of hydrophilic molecules and echo the computational research on protein active sites. The unique feature of combining hydrogen-bonding sites into a hydrophobic cavity also leads to thermodynamic consequences: a dominated enthalpy, a weak enthalpy-entropy compensation, and a positive solvent isotope effect. In addition, a good guest for these molecular tubes should meet the following criteria: a) the heteroatoms in the guest should be 64


9


complementary to the hydrogen-bonding sites in the cavity in terms of orientation, distance, and number; b) on this basis, the hydrophobic group of the guest should be large enough to expel all the cavity water molecules and maximize the hydrophobic effect, but not too large to cause any steric repulsion with the cavity walls; the dipole moment should be low. Following these guidelines, a binding constant as high as 106 M-1 was achieved with 2-phenyl-1,3-dioxolane (4). This suggests extremely strong binding with synthetic receptors is not limited to highly hydrophobic guest molecules3b but may also be achieved with hydrophilic molecules. Vice versa, the experience gained here can be used to design an efficient and selective receptor for a certain biologically or environmentally relevant hydrophilic molecule. First, a deep hydrophobic cavity with complementary size and shape is needed. Second, the heteroatoms or polar groups in the hydrophilic molecule should be satisfied by hydrogen-bonding sites or other polar binding sites. More complementary hydrogen bonds or polar interactions would lead to a higher selectivity. Last, these polar interactions should be located inside the deep hydrophobic cavity to experience a nonpolar environment and avoid water competition. The endo-functionalized molecular tubes presented here are unprecedented in terms of binding ability and binding mechanism and are complementary to conventional macrocyclic receptors. Therefore, we believe the present research lays a basis for their further applications, for example, in sensing,47,48 catalysis, self-assembly, molecular machinery, and materials science. Moreover, the cavities of these molecular tubes closely resemble protein binding pockets. The conclusions obtained here should also be helpful in understanding molecular recognition in complex biological systems.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental details, 1H NMR spectra of the complexes, computational details, NMR titration data, fluorescence titration data, ITC titration data, and single-crystal X-ray data. Crystallographic data for pyrazine@2a Crystallographic data for DMF@2a Crystallographic data for pyrrole@2a Crystallographic data for thiazole@2a Crystallographic data for imidazole@2a Crystallographic data for benzene@2a Crystallographic data for EA@2b Crystallographic data for N-ethylacetamide@2b Crystallographic data for DMC@2b Crystallographic data for dimethoxymethane@2b Crystallographic data for DEA@2b Crystallographic data for MDO@2b Crystallographic data for 1,4-dioxene@2b Crystallographic data for pyrazine@2b Crystallographic data for pyrrole@2b

AUTHOR INFORMATION Corresponding Author *[email protected]

ORCID

Page 10 of 12

Wei Jiang: 0000-0001-7683-5811 Georg Schreckenbach: 0000-0002-4614-0901

Author Contributions ¶

H.Y., H.K., X.-B.Z.: These authors contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This research was financially supported by the National Natural Science Foundation of China (Nos. 21572097, 21772083, 21822104; WJ), the Shenzhen Special Funds (KQJSCX20170728162528382, JCYJ20170307105848463; WJ), and the Natural Sciences and Engineering Research Council of Canada (NSERC, Discovery Grant; GS). We thank SUSTCMCPC for the support with instruments.

REFERENCES

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Molecular Recognition of Hydrophilic Molecules in Water by

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