Binding Properties of a Dinuclear Zinc(II) Salen-Type Molecular Tweezer with a Flexible Spacer in the Formation of Lewis Acid-Base Adducts with Diamines

inorganics

Article Binding Properties of a Dinuclear Zinc(II) Salen-Type Molecular Tweezer with a Flexible Spacer in the Formation of Lewis Acid-Base Adducts with Diamines

Gabriella Munzi , Giuseppe Consiglio , Salvatore Failla and Santo Di Bella *

Dipartimento di Scienze Chimiche, Università di Catania, I-95125 Catania, Italy; [email protected] (G.M.); [email protected] (G.C.); [email protected] (S.F.) * Correspondence: [email protected]

Abstract: In this paper we report the binding properties, by combined 1H NMR, optical absorption, and fluorescence studies, of a molecular tweezer composed of two Zn(salen)-type Schiff-base units connected by a flexible spacer, towards a series of ditopic diamines having a strong Lewis basicity, with different chain length and rigidity. Except for the 1,2-diaminoethane, in all other cases the formation of stable 1:1 Lewis acid-base adducts with large binding constants is demonstrated. For α,ω-aliphatic diamines, binding constants progressively increase with the increasing length of the alkyl chain, thanks to the flexible nature of the spacer and the parallel decreased conformational strain upon binding. Stable adducts are also found even for short diamines with rigid molecular structures. Given their preorganized structure, these latter species are not subjected to loss of degrees of freedom. The binding characteristics of the tweezer have been exploited for the colorimetric and fluorometric selective and sensitive detection of piperazine. Citation: Munzi, G.; Consiglio, G.; Failla, S.; Di Bella, S. Binding Keywords: zinc(II) complexes; Schiff-bases; molecular tweezers; Lewis acid-base adducts Properties of a Dinuclear Zinc(II) Salen-Type Molecular Tweezer with a Flexible Spacer in the Formation of Lewis Acid-Base Adducts with Diamines. Inorganics 2021, 9, 49. 1. Introduction https://doi.org/10.3390/ “Molecular tweezers” refer to bifunctional molecular receptors characterized by the inorganics9060049 presence of two binding sites connected with a more or less rigid spacer [1,2]. They have the ability to form complexes with a substrate molecule, resembling a tweezer holding an Academic Editor: Isabel Correia object. Depending on the nature of the binding sites and on the conformational rigidity of the spacer, they find various applications such as in molecular recognition [1,3], in- Received: 27 April 2021 cluding biomolecules [4–6], or fullerenes [7], enzyme inhibition or prevention of protein Accepted: 11 June 2021 aggregation [8–10], catalysis [11], switchable molecular tweezers [12,13], electrochemical Published: 16 June 2021 switches [14,15], and as building blocks for supramolecular nanostructures [16,17]. Various molecular tweezers have been synthesized as hosts for guest molecules. Publisher’s Note: MDPI stays neutral Among them, glycoluril- [1,2] or porphyrin-based [3] tweezers are those most studied. with regard to jurisdictional claims in The latter have been involved in various investigations for their ability to bind ditopic published maps and institutional affil- species, e.g., for configuration [18,19] and chirogenesis [20–23] studies, and for the devel- iations. opment of sensors targeting specific molecules [24], including chiral species [25,26]. More- over, the binding behavior with ditopic guests of different length and rigidities has also been explored [27–30]. Zn(salen)-type Schiff-base complexes have recently been investigated for their sensing Copyright: © 2021 by the authors. properties [31–33], mostly related to their Lewis acidic character [34]. These complexes Licensee MDPI, Basel, Switzerland. easily coordinate Lewis bases with formation of Lewis acid-base adducts, and this process This article is an open access article is accompanied by relevant changes of their spectroscopic properties. Among them, deriva- distributed under the terms and tives from the 2,3-diaminomaleonitrile, Zn(salmal) [35,36], are those mostly studied for conditions of the Creative Commons sensing a variety of Lewis bases [37–44]. Attribution (CC BY) license (https:// Recently, a dinuclear Zn(salmal) Schiff-base complex (1, Scheme1) whose units are con- creativecommons.org/licenses/by/ nected with a non-conjugated, flexible spacer, has been synthesized and characterized [45]. 4.0/).

Inorganics 2021, 9, 49. https://doi.org/10.3390/inorganics9060049 https://www.mdpi.com/journal/inorganics Inorganics 2021, 9, 49 2 of 13

Inorganics 2021, 9, 49 2 of 13

Recently, a dinuclear Zn(salmal) Schiff-base complex (1, Scheme 1)whose units are connectedRecently, with a nondinuclear-conjugated, Zn(salmal) flexible Schiff spacer,-base has complex been synthesized (1, Scheme and 1)whose characterized units are It[45].connected has Itbeen has beenwith found founda non that- conjugated,that in non-coordinating in non- flexiblecoordinating spacer, solvents solvents has1 beenis 1 stabilized issynthesized stabilized by thebyand the formationcharacterized formation of intramolecularof[45]. intramolecular It has been aggregates, foundaggregates, that which in which non hardly- coordinatinghardly deaggregate deaggregate solvents by by 1 addition additionis stabilized of of monotopicmonotopic by the formation LewisLewis bases.of intramolecular However, However, in inaggregates, the presence which of stronghardly ditopicdeaggregate Lewis by bases, bases, addition such of as asmonotopic diamines, diamines, Lewis the the complexbases. However, easily deaggregates in the presence with formation of strong ofditopic 1:1 adducts, Lewis bases, thus acting such asas aa diamines, “molecular“molecular the tweezer”.complex easilyDeaggregation Deaggregation deaggregates is is accompanied with formation by relevantof 1:1 adducts, opticaloptical thus absorption acting as changes a “molecular and aa substantialtweezer”. Deaggregation enhancement of is theaccompanied ﬂuorescence.fluorescence. by Therefore, relevant optic 1 hasal beenbeenabsorption investigatedinvestigated changes forfor and thethe a selectivesubstantial and enhancement sensitive detection of the ofof fluorescence. somesome biogenicbiogenic Therefore, diaminesdiamines 1 [[46].46has]. been investigated for the selective and sensitive detection of some biogenic diamines [46].

Scheme 1. 1. StructureStructure of of the the dinuclear dinuclear complex complex1. 1.As the dinuclear aggregate complex 1 acts as a “molecularScheme 1. tweezer”Structure upon of the deaggregation, dinuclear complex this is 1an.As unusual the dinuclear feature aggregatecompared complexTable 1. in1 actsthe for- as a mation“molecularAs of the Lewis tweezer” dinuclear acid-base upon aggregate adducts, deaggregation, complexit will not this 1beacts issubjected an as unusual a “molecular to binding feature as tweezer”compared a consequence upon Table deaggrega-of1. ain specific the for- tion,conformationmation this of is Lewis an of unusual the acid Lewis-base feature base. adducts, Rather, compared it will the not ability to be conventional subjected of the Lewis to tweezersbinding base to asbind characterized a consequence the aggregate by of bindingcoulda specific be sitesrelatedconformation kept to its separate basicity of the by Lewisand a spacer. to base. the stability Thus,Rather, starting theof the ability adduct. from of the the It Lewisis defined thus base interesting aggregate to bind tothe1 investigate, aggregate in the formation thecould fea- be ofturesrelated Lewis affecting to acid-base its basicitythe binding adducts, and interactionsto the it will stability not between be of subjectedthe thadduct.e aggregate to It binding is thus molecular interesting as a consequence tweezer to investigate 1, having of a specific athe flexi- fea- conformationbletures spacer, affecting and ofthethe the structurebinding Lewis interactions of base. the ditopic Rather, between Lewis the ability bases.the aggregate of the Lewis molecular base tweezer to bind 1 the, having aggregate a flexi- couldble spacer, be related and the to structure its basicity of the and ditopic to the Lewis stability bases. of the adduct. It is thus interesting to investigateThe aim the of features this work affecting is to study, the binding through interactions 1H NMR, between UV/vis, the and aggregate fluorescence molecular spec- tweezertroscopies,The1, aim having the of binding this a flexible work interactions spacer,is to study, and of thethrough the structure tweezer 1H NMR, of1 thewith UV/vis, ditopic diamines Lewisand offluorescence bases. different chain spec- lengthtroscopies,The and aim rigidity, the of this binding to work better interactions is to understand study, through of their the tweezer1 LewisH NMR, acid 1 UV/vis,with-base diamines interactions. and fluorescence of d ifferent spectro- chain scopies,length and the bindingrigidity, interactionsto better understand of the tweezer their Lewis1 with acid diamines-base interactions. of different chain length and2. Results rigidity, and to Discussion better understand their Lewis acid-base interactions. 2. ResultsTo study and the Discussion binding of various diamines to the molecular tweezer 1, either ali- 2. Results and Discussion phatic,To alicyclic, study the and binding aromatic of diamines various diamines were considered to the molecular (Scheme 2 tweezer). In particular, 1, either the ali- flexiblephatic,To studyprimaryalicyclic, the α bindingand,ω-aliphatic aromatic of various diamines, diamines diamines NH were2(CH to considered the2)nNH molecular2 (n = ( 2Scheme– tweezer12), were 2).1 ,Instudied, either particular, aliphatic, and the the alicyclic,resultsflexible comparedprimary and aromatic α ,ω with-aliphatic diamines those diamines, were related considered NH to2 (CH the (Scheme2 )nNH rigid2 2( n). diamines,= In 2 particular,–12), were piperazine thestudied, flexible and (PZ), pri- the mary1,4results-diazabicyclα,ω -aliphatic comparedo[2.2.2]octane diamines, with those NH (DABCO),2(CH related2)n NH and 2 to (n 4,4′ = the- 2–12),bipyridine rigid were diamines, studied, (BPY), and piperazine the the results semi -rigid com- (PZ), pared1,4-diazabicycl with thoseo[2 related.2.2]octane to the rigid (DABCO), diamines, and piperazine 4,4′-bipyridine (PZ), 1,4-diazabicyclo[2.2.2]octane (BPY), and the semi-rigid 1,2-bis(4-pyridyl)ethane0 (DPE). (DABCO),1,2-bis(4-pyridyl)ethane and 4,4 -bipyridine (DPE). (BPY), and the semi-rigid 1,2-bis(4-pyridyl)ethane (DPE).

Scheme 2. Structure of investigated diamines. SchemeScheme 2. 2.Structure Structure of of investigated investigated diamines. diamines.

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UV/vis optical absorption and fluorescence spectral data and binding constants for the formation of (1:1) 1·diamine adducts (equilibrium (1)) are reported in Table1. Spectropho- Inorganics 2021, 9, 49 3 of 13 tometric and spectrofluorometric titrations for the representative 1,10-diaminodecane are reported in Figures1 and2. UV/vis optical absorption and fluorescence spectral data and binding constants for 1 (soln) + diamine (soln) 1 diamine (soln) (1) the formation of (1:1) 1·diamine adducts (equilibrium (1)) are reported in Table 1. Spec- trophotometric and spectrofluorometric titrations for the representative 1,10-diaminodecaneIn all instances, are reported the binding in Figures of diamines1 and 2. to 1 involves an increase of the optical absorption band centered at λmax = 580 nm and an enhancement of fluorescence intensity ∼ 1 (soln) + diamine (soln) ⇋ 1‧diamine (soln) (1) at λmax = 614 nm (e.g., the fluorescence quantum yield, φ, increases from 0.03 to 0.29 on switchingIn all instances, from 1 to the the bind adducting of withdiamines 1,10-diaminodecane). to 1 involves an increase Moreover, of the optical with theab- exception of diaminoethane,sorption band centered optical at λ absorptionmax = 580 nm spectraand an enhancement show the presence of fluorescence of multiple intensity isosbestic at points, indicativeλmax  614 nm of the(e.g., formation the fluorescence of species quantum with yield, a defined ϕ, increases stoichiometry. from 0.03 to 0.29Job’s on plot analyses switching from 1 to the adduct with 1,10-diaminodecane). Moreover, with the exception clearly indicate the formation of 1:1 adducts. of diaminoethane, optical absorption spectra show the presence of multiple isosbestic points, indicative of the formation of species with a defined stoichiometry. Job’s plot a Tableanalyses 1. Bindingclearly indicate constants the formation and optical of spectroscopic1:1 adducts. data for investigated 1·diamine adducts in chloroform solution. Table 1. Binding constants and optical spectroscopic data for investigated 1·diamine adducts a in chloroformDiamine solution. log K Absorption λmax (nm) Emission λmax (nm) Diamine1 log K Absorption λ582max (nm) Emission λmax (nm) 625 PZ1 5.4 ± 0.1582 580625 618 DABCOPZ 5.65.4± ± 0.20.1 580 580618 614 DPEDABCO 4.05.6± ± 0.10.2 580 579614 614 DPE 4.0 ± 0.1 579 614 2.1 ± 0.2 (K1) BPY 2.1 ± 0.2 (K1) 580 611 BPY 3.6 ± 0.2 (K2) 580 611 3.6 ± 0.2 (K2) 1,2-Diaminoethane - 583 614 1,2-Diaminoethane - 583 614 1,3-Diaminopropane 2.9 ± 0.1 580 614 1,3-Diaminopropane 2.9 ± 0.1 580 614 b ± 1,4-Diaminobutane1,4-Diaminobutane b 4.34.3 ± 0.10.1 580 580618 618 b 1,5-Diaminopentane1,5-Diaminopentane b 5.05.0± ± 0.20.2 580 580618 618 1,6-Diaminohexane1,6-Diaminohexane 5.15.1± ± 0.10.1 580 580614 614 1,8-Diaminooctane1,8-Diaminooctane 6.46.4± ± 0.10.1 587 587616 616 1,10-Diaminodecane1,10-Diaminodecane 6.26.2± ± 0.20.2 580 580614 614 1,12-Diaminododecane1,12-Diaminododecane 5.95.9± ± 0.20.2 580 580614 614 aa For comparison, 1·(pyridine)2; 2: λmax = 579 nm (absorption); λmax = 613 nm (emission); log K1 = 2.35; For comparison, 1·(pyridine)2; λmax = 579 nm (absorption); λmax = 613 nm (emission); log K1 = 2.35; log K2 = 3.58; fromlog K ref.2 = 3.58; [45]. fromb from ref. ref. [45]. [46 b f].rom ref. [46].

b) 0.18 a) 0.16 1.6 0.14 0.12

]

)

 0.10

( 1.4 0 0.08

[ 0.06

1.2 A=A- 0.04 0.02 1.0 0.00 0.0 0.2 0.4 0.6 0.8 1.0 0.8 1,10-Diaminodecane c) 1.7 1.6 Absorbance 0.6 1.5 R2 = 0.997 1.4 0.4 1.3 1.2 0.2 1.1 1.0

Absorbance@580nm 0.0 0.9 0.8

300 400 500 600 700 0 10 20 30 40 50 Wavelength (nm) [1,10-Diaminodecane] (M)

Figure 1. (a) Optical absorption titration curves of 1 (15 µM solution in CHCl3) with addition of Figure 1. (a) Optical absorption titration curves of 1 (15 µM solution in CHCl3) with addition of 1,10-diaminodecane. The concentration of 1,10-diaminodecane added varied from 0 to 50 µM. (b) 1,10-diaminodecane. The concentration of 1,10-diaminodecane added varied from 0 to 50 µM. Job’s plot for the binding of 1 with 1,10-diaminodecane. The total concentration of 1 and (b) Job’s plot for the binding of 1 with 1,10-diaminodecane. The total concentration of 1 and 1,10-diaminodecane is 15 µM. (c) Variation of the absorbance at 580 nm as a function of the concentration of 1,10-diaminodecane added and ﬁt of the binding isotherm with Equation (1) (red line). Inorganics 2021, 9, 49 4 of 13

Inorganics 2021, 9, 49 4 of 13 1,10-diaminodecane is 15 μM. (c) Variation of the absorbance at 580 nm as a function of the concentration of 1,10-diaminodecane added and fit of the binding isotherm with Equation 1 (red line).

3500 3500 3000

2500

3000 2000

1500

1000 2500 Intensity@614 nm 500

0 0 10 20 30 40 50 2000 [1,10-Diaminodecane] ( M)

1500

Intensity (a.u.) 1000

500

0 550 600 650 700 750 Wavelength (nm)

FigureFigure 2. 2.FluorescenceFluorescence titration titration curves curves of 1 of (151 (15µM µsolutionM solution in CHCl in CHCl3; λexc3 ;=λ 516exc nm)= 516 with nm) addition with ad- ofdition 1,10-diaminodecane. of 1,10-diaminodecane. The concentration The concentration of 1,10-diaminodecane of 1,10-diaminodecane added varied added from varied 0 to from50 µM. 0 to Inset:50 µ M.variationInset: variation of the fluorescence of the ﬂuorescence intensity intensity at 614 at nm 614 as nm a as function a function of of the the concentration concentration of of 1,101,10-diaminodecane-diaminodecane added. added.

2.1.2.1. α,ωα,ω-Aliphatic-Aliphatic Diamines Diamines AsAs is is shown shown in in Table Table 1,1, a a substantial variation variation of of the the binding binding constants constants with with the the chainchain length length is is observed. observed. Despite the the analogous analogous Lewis Lewis basicity basicity [47 [47]] along along this this investigated investi- gatedseries series of aliphatic, of aliphatic, linear linear primary primary diamines, diamines, binding binding constants constants span span over over more more than tha threen threeorders orders of magnitude. of magnitude. While While shorter shorter diamines diamines are characterized are characterized by relatively by relatively low binding low bindingconstants, constants, the increasing the increasing of the chain of length the chain parallels length an increaseparallels of an binding increas constante of binding values. constantLargest values. binding Largest constants binding are reached constants with are the reached 1,8-diaminooctane, with the 1,8 and-diaminooctane then remain almost, and thenunchanged, remain almost even if unchanged, slightly smaller, even on if slightly further increasesmaller, ofon the further chain increase length. of the chain 1 length. H NMR titration studies further support the formation of 1:1 adducts. The titration for1 theH NMR representative titration studies 1,10-diaminodecane further support is reportedthe formation in Figure of 1:13. adducts. In particular, The titration after the foraddition the representative of half stoichiometric 1,10-diaminodecane amount of is 1,10-diaminodecane reported in Figure 3. to In a particular, CDCl3 solution after the of 1 , the 1H NMR spectrum shows some changes with the appearance of new broad signals. addition of half stoichiometric amount of 1,10-diaminodecane to a CDCl3 solution of 1, 1 theA 1 completeH NMR spectrum variation shows of the someH NMR changes spectrum, with the with appearance the presence of new of broad broad signals. signals, A is completeobserved variation after the of addition the 1H NMR of a stoichiometric spectrum, with amount the presence of 1,10-diaminodecane. of broad signals, Finally,is ob- upon the addition of 4-fold molar excess of 1,10-diaminodecane the spectrum evolves served after the addition of a stoichiometric amount of 1,10-diaminodecane.0 Finally, upontowards the aaddition set of sharp of 4- signals,fold molar except excess for the of down-field 1,10-diaminodecane shifted H3 theand spectrum H3 protons evolves which remain slightly broad, indicative of the formation of a defined 1:1: adduct. Moreover, the towards a set of sharp signals, except for the down-field shifted H3 and H3′ protons which doublet of doublet benzylic proton signals, H , of the aggregate complex 1 becomes a remain slightly broad, indicative of the formation5 of a defined 1:1: adduct. Moreover, the sharp singlet, indicating that the restricted rotation around the benzylic bonds is no longer doublet of doublet benzylic proton signals, H5, of the aggregate complex 1 becomes a operating in the adduct. sharp singlet, indicating that the restricted rotation around the benzylic bonds is no 1,2-Diaminoethane behaves quite differently. In fact, starting from 10 µM solutions longer operating in the adduct. of 1 a detectable variation of optical absorption or fluorescence spectra occurs after the 1,2-Diaminoethane behaves quite differently. In fact, starting from 10 μM solutions addition of ca. 2-fold molar excess of diaminoethane, while the saturation point is reached of 1 a detectable variation of optical absorption or fluorescence spectra occurs after the by the addition of ca. 800-fold molar excess, unlike longer diamines which form 1:1 adducts addition of ca. 2-fold molar excess of diaminoethane, while the saturation point is with 1 by addition of stoichiometric amounts. Moreover, in contrast with longer diamines, reached by the addition of ca. 800-fold molar excess, unlike longer diamines which form optical absorption spectra do not show any isosbestic point. These observations suggest 1:1 adducts with 1 by addition of stoichiometric amounts. Moreover, in contrast with the formation of multiple, instead of single, adducts (e.g., 1:2 adducts), likely favored by longerthe presence diamines, of theoptical large absorption stoichiometric spectra excess do ofnot diamine. show any isosbestic point. These observations suggest the formation of multiple, instead of single, adducts (e.g., 1:2 adducts), likely favored by the presence of the large stoichiometric excess of diamine. As binding constants for the formation of 1·diamine adducts reflect the relative stability of the adducts with respect to the aggregate [48], given the analogous Lewis basic-

Inorganics 2021, 9, 49 5 of 13

ity along the series of diamines and the entropic cost upon binding the diamine to 1, the increasing binding constants with the increased length of diamines can be related to an increased stability of the intramolecular cyclic adducts. In view of the flexibility of the spacer in the tweezer 1, which in principle can accommodate almost any ditopic Lewis base, the different binding constants along the series could be attributed to a larger entropic cost of the loss of degrees of freedom for diamines with a shorter alkyl chain, while Inorganics 2021, 9, 49 the involved longer α,ω-diamines are not subjected to conformational strain upon5 bind- of 13 ing, resulting in larger intramolecular cyclic adducts, also with gain of degrees of freedom of the flexible spacer of the tweezer.

H4 H4′ H6 H1+H1′ H H3′ H +H ′ 3 H (a) 2 2 5

(b)

(c)

H5 H4 H6 H4′ H3 H3′ (d)

δ (ppm)

1 FigureFigure 3. 3. H1H NMR NMR titration titration spectra spectra of of1 1(50 (50µ μMM in in CDCl CDCl3 3( a(a)))) with with addition addition of of 1,10-diaminodecane. 1,10-diaminodecane. TheThe concentration concentration ofof 1,10-diaminodecane1,10-diaminodecane added was 25 25 μµMM( (bb),), 50 50 μµMM( (cc),), and and 200 200 μMµM( (d).d ).For For as- assignmentsignment of of 1H1H NMR NMR signals signals of of the the aggregate aggregate 11. .Adapted Adapted from from ref. ref. [45]. [45].

AsIn binding comparison constants to host for the–guest formation studies of 1 involving·diamine adducts glycoluril reflect- or the porphyrin relative stabil--based itytweezers of the adducts with ditopic with guests respect of to different the aggregate length, [48 1], behaves given the quite analogous different Lewisly, being basicity char- alongacterized the seriesby increasing of diamines binding and constants the entropic with cost increasing upon binding chain length the diamine of diamines. to 1, the In increasingfact, it has binding been constants found that with most the increasedof these investigate length of diaminesd tweezers, can be having related rigid to an or increasedsemi-flexible stability spacers, of the show intramolecular a preference cyclicfor a particular adducts. Inguest, view rather of the than flexibility for shorter of the or spacerlonger in ones. the tweezerThis has 1been, which associated in principle with canthe guest accommodate best matching almost the any distance ditopic between Lewis base,the binding the different sites bindingof the tweezer constants [27 along–30,49 the–51 series]. could be attributed to a larger entropic cost of the loss of degrees of freedom for diamines with a shorter alkyl chain, while the involved2.2. Rigid longer Diaminesα,ω -diamines are not subjected to conformational strain upon binding, resulting in larger intramolecular cyclic adducts, also with gain of degrees of freedom of The binding interaction for the formation of 1·diamine adducts is also affected by the the flexible spacer of the tweezer. rigidity of the diamine. PZ is a cyclic secondary diamine with a N-N distance comparable In comparison to host–guest studies involving glycoluril- or porphyrin-based tweezers to that of 1,2-diaminoethane. In spite of this, PZ forms stable 1:1 adducts with 1, with a with ditopic guests of different length, 1 behaves quite differently, being characterized large binding constant (Table 1), especially if compared to that of aliphatic diamines with by increasing binding constants with increasing chain length of diamines. In fact, it has beenshorter found chain that length most of(n these≤ 4). DABCO investigated is a bicyclic tweezers, tertiary having diamine rigid or whose semi-flexible N-N distance spacers, is showcomparable a preference to that for of aPZ. particular It has been guest, widely rather used than to for study shorter the orbinding longer characteristics ones. This has of beenporphyrin associated-based with tweezers the guest [22,30,52 best matching–54]. Again, the distance DABCO between binds easily the binding with 1sites with of a thebinding tweezer constant [27–30 sli,49ghtly–51]. higher than that of PZ. This is consistent with the greater Lewis basicity of the tertiary alicyclic DABCO with respect to the secondary alicyclic PZ [47]. 2.2. RigidIt therefore Diamines turns out that the preorganized structure of PZ and DABCO favors the formationThe binding of stable interaction adducts for because, the formation except offor1 the·diamine entropic adducts cost upon is also binding affected the by thedia- rigidity of the diamine. PZ is a cyclic secondary diamine with a N-N distance comparable to that of 1,2-diaminoethane. In spite of this, PZ forms stable 1:1 adducts with 1, with a large binding constant (Table1), especially if compared to that of aliphatic diamines with shorter chain length (n ≤ 4). DABCO is a bicyclic tertiary diamine whose N-N distance is comparable to that of PZ. It has been widely used to study the binding characteristics of porphyrin-based tweezers [22,30,52–54]. Again, DABCO binds easily with 1 with a binding constant slightly higher than that of PZ. This is consistent with the greater Lewis basicity of the tertiary alicyclic DABCO with respect to the secondary alicyclic PZ [47]. Inorganics 2021, 9, 49 6 of 13

InorganicsInorganics 2021 2021, 9, ,9 49, 49 6 6of of 13 13

It therefore turns out that the preorganized structure of PZ and DABCO favors the formation of stable adducts because, except for the entropic cost upon binding the diamine minetomine1, theseto to 1, 1, these speciesthese species species are not are are subjected not not subjected subjected to loss to to ofloss loss degrees of of degrees degrees of freedom, of of freedom, freedom, contrary contrary contrary to aliphatic to to ali- ali- phaticdiaminesphatic diamines diamines with short with with alkylshort short chain. alkyl alkyl chain. chain. 11 1HHH NMR NMRNMR titrations titrations usingusing using DABCODABCO DABCO as as as titrant titrant titrant suggest suggest suggest the the the formation formation formation of stableof of s tsablet 1:1able adducts1 1:1:1 ad- ad- ductsevenducts foreven even alicyclic for for alicyclic alicyclic diamines diamines diamines (Figure (Figure (Figure4). In this4). 4). In In case, this this however,case, case, however, however, when when halfwhen stoichiometric half half stoichio- stoichio- amount of DABCO is added to CDCl solution3 of 1, two sets of signals are evident in metricmetric amount amount of of DABCO DABCO is is added added to to CDCl 3CDCl3 solution solution of of 1 1, ,two two sets sets of of signals signals are are evident evident 1 inthein the the spectrum. spectrum. spectrum. This This This indicates indicates indicates the the the presence presence presence in in in solution solutio solutionn ofof of thethe the aggregateaggregate aggregate complexcomplex complex 1 1 and and its its adduct with DABCO, in a slow equilibrium on the NMR time scale. Moreover, from the adductadduct with with DABCO, DABCO, in in a a slow slow equilibrium equilibrium on on the the NMR NMR time time scale. scale. Moreover, Moreover, from from the the comparison of the signal of H55protons, a sharper singlet is observed for the adduct with comparisoncomparison of of the the signal signal of of H H5 protons, protons, a a sharper sharper singlet singlet is is observed observed for for the the adduct adduct with with 1,10-diaminodecane, with respect to the broad signal for that with DABCO. This suggests a 1,101,10-diaminodecane,-diaminodecane, w withith respect respect to to the the broad broad signal signal for for that that with with DABCO. DABCO. This This suggests suggests greater mobility of benzyl hydrogens in the larger intramolecular cyclic 1·diaminodecane aa greater greater mobility mobility of of benzyl benzyl hydrogens hydrogens in in the the larger larger intramolecularintramolecular cycliccyclic adduct compared to those of the 1·DABCO adduct (Figure5). 11·diaminodecane·diaminodecane adduct adduct compared compared to to those those of of the the 1 1·DABCO·DABCO adduct adduct (Figure (Figure 5). 5).

H H4′ H 4 H4′ H6 4 H6 H ′ H1+H1′ H3H ′ 3 H1+H1′ H +H ′H3 3 H +H2 ′ 2 HH5 (a()a) 2 2 5

(b()b)

(c()c)

H4 H4′ H4 H4′

H3′ H6 H3′ H6 H H5 H 3 H5 (d()d) 3

δ (ppm) δ (ppm)

1 Figure 4. 1 H NMR titration spectra of 1 (50 µM in CDCl (a)) with addition of DABCO. The Figure 4.1 H NMR titration spectra of 1 (50 μM in CDCl3 (a3)) with addition of DABCO. The con- Figure 4. H NMR titration spectra of 1 (50 μM in CDCl3 (a)) with addition of DABCO. The con- concentration of DABCO added was 25 µM(b), 100 µM(c), and 200 µM(d). centrationcentration of of DABCO DABCO added added was was 2 52 5μ μMM ( b(b),), 10 100 0μ μMM ( c(),c), and and 200 200 μ μMM ( d(d).).

(a()a ) (b(b) )

FigureFigureFigure 5 5..5 (.( a(a)a) )Modeling ModelingModeling (PM3 (PM3,(PM3, using,using using thethe the HyperChemHyperChem HyperChem SoftwareSoftware Software ( (8.0)) 8.0(8.0))) )of of of the thethe 11 ·diaminodecane1·diaminodecane·diaminodecane adduct adductadduct and (b) modeling of the 1·DABCO adduct. andand ( (bb)) modeling modeling of of the the 1·DABCO 1·DABCO adduct. adduct.

TheTheThe structure structure of of of DPE DPE DPE is is more is more more rigid rigid rigid than than than that that thatof of α,ω α,ω of-aliphatic-αaliphatic,ω-aliphatic diamines diamines diamines because because because of of the the presenceofpresence the presence of of two two of heterocyclic heterocyclic two heterocyclic aromatic aromatic aromatic rings rings rings linked linked linked by by an an by ethyl ethylan ethyl group. group. group. In In the the In thean-an- tiantiti-conformation-conformation-conformation,, ,a a N aN- N-NN-N distance distance distance of of of9.3 9.3 9.3Å Å can Åcan can be be beestimated, estimated, estimated, slightly slightly slightly longer longer longer than than than that that that of of 1,61,6-diaminohexane-diaminohexane (8.7 (8.7 Å Å ). ). However, However, the the binding binding constant constant of of DPE DPE results results are are one one order order ofof magnitude magnitude lower lower than than that that of of 1,6 1,6-diaminohexane.-diaminohexane. This This can can be be attributed attributed to to a a higher higher

Inorganics 2021, 9, 49 7 of 13

Inorganics 2021, 9, 49 7 of 13 of 1,6-diaminohexane (8.7 Å). However, the binding constant of DPE results are one order of magnitude lower than that of 1,6-diaminohexane. This can be attributed to a higher con- conformationalformational strain strain upon upon binding binding DPE DPE to 1 , to in comparison1, in comparison with thewith flexible the flexible diaminohexane. dia- minohexBPYane. was also investigated as rigid diamine. Spectrophotometric titrations again indicateBPY thewas formation also investigated of a defined as rigid species; diamine. by Spectrophotometric the presence of multiple titrations isosbestic again in- points, dicatehowever, the formation the saturation of a defined point is species reached; by with the ca.presence a 500-fold of multiple molar excessisosbestic of BPY.points, In this however,case the bindingthe saturation isotherm point is is fitted reached with with a model ca. a 500 involving-fold molar a 1:2 excess adduct of BP (equilibriaY. In this (2)), caseinstead the ofbinding a 1:1 adductisotherm (equilibrium is fitted with (1)). a model involving a 1:2 adduct (equilibria (2)), instead of a 1:1 adduct (equilibrium (1)). 1 (soln) + BPY (soln) 1·BPY (2) 1 (soln) + BPY (soln) ⇋ 1‧BPY (2) 1·BPY (soln) + BPY (soln) 1·(BPY)2 (soln) (2’) 1‧BPY (soln) + BPY (soln) ⇋ 1‧(BPY)2 (soln) (2′) Even if the ditopic BPY is expected to possess a strong Lewis basicity comparable to Even if the ditopic BPY is expected to possess a strong Lewis basicity comparable to pyridine,pyridine, it it behaves behaves as as a amonotopic monotopic species. species. Deaggregation Deaggregation of 1 of with1 with pyridine pyridine gave gave the the samesame results results (Table (Table 1)1)[ [45].45]. 2.3. Sensing Piperazine 2.3. Sensing Piperazine 1 TheThe molecular molecular tweezer tweezer 1 cancan be be used used as asa suitable a suitable chemodosimeter chemodosimeter for the for detection the detection ofof piperazine. piperazine. PZ PZ possesses possesses important important pharmacological pharmacological properties properties and andis used, is used, together together with its salts, as an anthelmintic [55], in industrial gas treatments such as CO capture with its salts, as an anthelmintic [55], in industrial gas treatments such as CO2 capture2 systemsystem [56,57], [56,57], andand also also as as the the precursor precursor for fora class a class of psyc of psychogenichogenic drugs drugs [58,59]. [58 Pipera-,59]. Piper- zineazine may may cause cause allergic allergic dermatitis dermatitis [60], [60 and], and it has it has been been demonstrated demonstrated that, that, although although not not extremelyextremely toxic, toxic, itit has has a alow low biodegradability biodegradability [61] [61. Detection]. Detection of PZ of is PZ thus is thus relevant relevant for for environmentenvironment monitoring monitoring and and protection protection [62]. [62 ]. TheThe tweezer tweezer 1 1allowsallows both both the the colorimetric colorimetric and and fluorometric fluorometric selective selective and andsensitive sensitive detectiondetection of of PZ. PZ. A A calculated calculated limit limit of ofdetection detection (LOD (LOD)) down down to 0.76 to 0.76µM µandM and0.33 0.33µM isµ M is obtobtainedained from from the the spectrophotometric spectrophotometric and and spectrofluorometric spectrofluorometric data, data,respectively, respectively, with a with lineara linear dynamic dynamic range range up to up 10to μM 10 (FiguresµM (Figures 6 and6 7). and These7). Thesevalues valuesare better are than better those than reportedthose reported in the literature in the literature using spectrophotometric using spectrophotometric methods methods[63–66]. Various [63–66]. other Various tech- other niquestechniques have have been been developed developed for the for detection the detection and quantitation and quantitation of piperazine, of piperazine, such as such HPLCas HPLC [67], [67 voltammetry], voltammetry [68], [ 68or], capillary or capillary electrophoresis electrophoresis [69]; [most69]; most of them, of them, however, however, requirerequire time time-consuming-consuming procedures. procedures. Therefore, Therefore, the the development development of simple of simple and and direc directt methodsmethods for for sensing sensing piperazine piperazine is ishighly highly desirable. desirable. In this In this regard, regard, only only a few a few optical optical chemosensorschemosensors are are reported reported in in the the literature literature for for the the selective selective detection detection of PZ of [70 PZ– [7270].– 72].

b) 1.7 1.6 a) 1.5 R2 = 0.998 1.6 1.4 1.3 1.4 1.2 1.1 1.2 1.0 Absorbance@580nm 0.9 1.0 0.8 0 10 20 30 40 50 60 [Piperazine] ( M) 0.8 c) 1.3

Absorbance Slope = 3.64E4 0.6 1.2 R2 = 0.999

0.4 1.1

1.0 0.2

Absorbance@580 nm 0.9 0.0 300 400 500 600 700 0.8 0 2 4 6 8 10 [Piperazine] ( M) Wavelength (nm)

FigureFigure 6. 6. (a(a) )Optical Optical absorption absorption titration titration curves curves of 1 of (151 (15µMµ solutionM solution in CHCl in CHCl3) with3) withaddition addition of PZ. of PZ. TheThe concentration concentration of of PZ PZ added added varied varied from from 0 to 0 to60 60 µM.µM. (b) ( bVariation) Variation of ofthe the absorbance absorbance at 580 at 580nm nmas as a afunction function of of the the concentration concentration of of PZ PZ added added and and ﬁt fit of of the the binding binding isotherm isotherm with with Equation Equation (1) 1 (red line). line). (c) Linear best fit in the linear dynamic range (weight given by data error bars). (c) Linear best ﬁt in the linear dynamic range (weight given by data error bars).

InorganicsInorganics 20212021, ,99, ,49 49 88 of of 13 13

b) 4000 3500 a) 4000 3000 Inorganics 2021, 9, 49 8 of 13 2500 3500 2000

1500

3000 Intensity@618nm 1000 b) 4000 500 3500 2500 0 a) 4000 3000 0 10 20 30 40 50 60 2500 [Piperazine] (M) 35002000 2000

1500 c) 1600

30001500 Intensity@618nm 1000 1400 Slope = 1.31E8

Intensity (a.u.) Intensity 500 R2 = 0.999 2500 1200 1000 0 0 10 20100030 40 50 60

618nm 2000 [Piperazine]800 (M) 500 600 c) 1600

1500 Intensity@ 1400 Slope =400 1.31E8

Intensity (a.u.) Intensity R2 = 0.999 0 1200 200 1000 1000 0 550 600 650 700 750 618nm 800 800 0 2 4 6 8 10 500 [Piperazine] (M) Wavelength (nm) 600 Intensity@ 400 0 200 Figure 7. (a) Fluorescence titration curves of 1 (15 µM solution0 in CHCl3; λ3 excexc= 515 nm) with addition Figure 7. (a) 550Fluorescence600 titration650 curves700 of750 1 (15 µ800M solution0 in2 CHCl4 6 ; λ8 =10 515 nm) with addi- µ [Piperazine] (M) tionofPZ. of PZ. The The concentration concentrationWavelength of of PZ PZ added (nm)added varied varied from from 0 0 to to 6060 µM.M. ((bb)) Variation of the the fluorescence ﬂuorescence intensityintensity at at 618 618 nm nm as as a a function function of of the the concentration concentration of of PZ PZ added. added. (c (c) )Linear Linear best best fit ﬁt in in the the linear linear Figuredynamicdynamic 7. (a range) rangeFluorescence (weight (weight titration given given curvesby by data data of error1 error (15 µ bars).M bars). solution in CHCl3; λexc = 515 nm) with addition of PZ. The concentration of PZ added varied from 0 to 60 µM. (b) Variation of the fluorescence intensity at 618 nm as a function of the concentration of PZ added. (c) Linear best fit in the linear dynamicTheThe range selectivity selectivity (weight given of of 1by1 towards towardsdata error PZbars). PZ was was proven proven by by performing performing competitive competitive exper experiments.iments. TheseThese were were conducted conducted by by mixing mixing a a solution solution of of 11 withwith PZ PZ (1:1 (1:1 molar molar ratio) ratio) and and a a 10 10-fold-fold molarmolarThe excess selectivity excess of of interferentof interferent 1 towards (FigurePZ (Figure was proven 8).8). These Theseby performing results results were competitive were then then compared exper comparediments. with with those those ob- Thesetainedobtained were by conducted byadding adding to by 1 to mixingeither1 either aPZ solution PZ in inan anof equimolar 1 equimolar with PZ (1:1amount, amount, molar ratio)or or the theand interferent interferenta 10-fold in in a a 10 10-fold-fold molarmolar excess excess. of interferent As potential (Figure interferents,8). These results some were monotopicthen compared species with those with ob- a strong Lewis tainedmolar by excess. adding As to potential1 either PZ interferents, in an equimolar some amount, monotopic or the interferent species within a 10 a- foldstrong Lewis ba- molarsicitybasicity excess.were were Asconsidered. considered.potential interferents, Pyridine Pyridine somewas was chosenmonotopic chosen as asspecies the the heterocyclic heterocyclicwith a strong aromatic Lewis aromatic ba- amine, amine, while while sicityisopropylamine,isopropylamine, were considered. diethylamine, diethylamine, Pyridine was and chosen triethylaminetriethylamine as the heterocyclic werewere chosen aromaticchosen as asamine, prototype prototyp whilee compounds compounds of isopropylamine,ofprimary, primary, secondary, diethylamine, secondary, and tertiary and and triethylamine amines. tertiary Moreover,were amines. chosen the as prototyp heteroditopicMoreover,e compounds the 4-amino-1-butanol, heteroditopic of4bearing- amino primary,- two1-butanol, different secondary, bearing coordinating and two tertiary different sites amines. with coordinating a different Moreover, sites Lewis the with basicity, heteroditopic a different was also Lewis considered. basic- 4-amino-1-butanol, bearing two different coordinating sites with a different Lewis basicity,As was shown also in considered. Figure8, very As shown small orin noFigure changes 8, very of small the absorbance or no changes at λ ofmax the= abso 580rb- nm ity, was also considered. As shown in Figure 8, very small or no changes of the absorb- anceare observedat λmax = 580 after nm the are addition observed of eachafter potentialthe addition interferent, of each especiallypotential interferent, for diethylamine espe- ance at λmax = 580 nm are observed after the addition of each potential interferent, espe- and triethylamine. Therefore, these data suggest that 1 can be considered a selective cially for for diethylamine diethylamine and and triethylamine. triethylamine. Therefore, Therefore, these data these suggest data that suggest 1 can be that 1 can be consideredreceptor towardsa selectivea selective PZ,receptor evenreceptor towards in the towards presencePZ, even PZ, in of theeven common presence in the aliphatic ofpresence common or ofali aromatic phaticcommon or monotopic aliphatic or or aromaticheteroditopic monotopic monotopic amines. or heteroditopic or heteroditopic amines. amines.

1+PZ (1:1) 1+PZ+interferent 1+PZ (1:1) (1:1:10) 1+interferent 1+PZ+interferent (1:10) (1:1:10) 1.4 1+interferent (1:10) 1.4 1.2 1.2 1.0

0.81.0

0.60.8

0.4

Absorbance@580nm 0.6 0.2 0.4

Absorbance@580nm 0.0 0.2 Pyridine DiethylamineTriethylamineAminobutanol 0.0 Isopropylamine Figure 8. Absorbance of 1 at 580 nm upon the addition of an equimolar amount (15 µM) of piperazine Pyridine DiethylamineTriethylamine µ (orange bars);Isopropylamine upon the addition of anAminobutanol equimolar amount (15 M) of piperazine with the presence of 10-fold molar excess (150 µM) of interferent (green bars); upon the addition of 10-fold molar excess (150 µM) of interferent (violet bars).

Inorganics 2021, 9, 49 9 of 13

3. Experimental Section 3.1. Materials and General Procedures All the chemicals used were purchased from Sigma-Aldrich (Darmstadt, Germany) and used as received. Complex 1 was synthesized and purified as previously reported [45]. Chloroform stabilized with amylene was used for optical absorption and fluorescence titrations. Before being used, it was purified as follows: dried on anhydrous K2CO3 for 2 h, filtered and stored over molecular sieves (3 Å) in the dark under argon atmo- sphere. Chloroform solutions of 1 were prepared by dissolving the compound in chloroform and filtering it through a 0.2 µm Teflon membrane filter. CDCl3 was stored over molecular sieves (3 Å).

3.2. Physical Measurements 1H NMR measurements were run at 27 ◦C on a Varian Unity S 500 (499.88 MHz for 1H) spectrometer. Tetramethylsilane was used as internal reference for all NMR experiments. Optical absorption spectra were recorded at room temperature with an Agilent Cary 60 spectrophotometer. Fluorescence spectra were recorded at room temperature using a JASCO FP-8200 spectrofluorometer (JASCO Europe). Spectrophotometric and fluorometric titrations were performed with a 1 cm path cell using 15 µM chloroform solutions of 1. Chloroform solutions of involved Lewis bases were added to the solution of 1 using Rainin (METTLER TOLEDO, Columbus, OH, USA) positive displacements pipettes. At least three replicate titrations were performed for each diamine. In fluorometric titrations, the wavelength of excitation was chosen in an isosbestic point. The fluorescence quantum yield was obtained using fluorescein (φF = 0.925) in 0.1 M NaOH as a standard. The absorbance value of the samples at and above the excitation wavelength was lower than 0.1 for 1 cm path length cuvettes.

3.3. Calculation of Binding Constants and Limit of Detection Binding constants, K, for the formation of 1 diamine adducts (equilibrium 1) were calculated by ﬁtting the binding isotherms, obtained from the plot of A vs. cA from spectrophotometric titration data, with Equation (1) [73,74].

1/2 Alim − A0 h 2 i A = A0 + c0 + cDA + 1/K − (c0 + cDA + 1/K) − 4c0cDA . (1) 2c0

where A0 is the initial absorbance of the solution having a concentration c0, A is the absorbance intensity after addition of a given amount of diamine (DA) at a concentration cDA, and Alim is the limiting absorbance reached in the presence of an excess of DA. Further details are reported elsewhere [46,48]. These calculated binding constants are comparable to those previously obtained by a multivariate analysis from spectrophotometric titrations of 1 with PZ, DPE, and 1,4-diaminobutane [45]. In the case of BPY, binding constants K1 and K2 for a 1:2 adduct (equilibria (2)) were calculated by ﬁtting the binding isotherm using Equation (35) of Ref. [73]. The limit of detection (LOD) was estimated, both from optical absorption or ﬂuores- cence data, according to IUPAC recommendations (Equation (2)) [75,76].

LOD = K × Sb/S (2)

where K = 3, Sb is the standard deviation of the blank solution, i.e., the absorbance or ﬂuorescence signal of 1, and S is the slope of the calibration curve obtained from the plot of the absorbance or ﬂuorescence intensity of 1 vs. the concentration of the DA added. Each point is related to the mean value obtained from at least three replicate measurements. Twenty blank replicates were considered. Inorganics 2021, 9, 49 10 of 13

4. Conclusions The binding properties of a molecular tweezer, composed of two Zn(salmal) units connected by a flexible spacer, towards a series of ditopic diamines having strong Lewis basicity have been explored by means of combined 1H NMR, optical absorption, and fluorescence studies. The formation of stable 1:1 Lewis acid-base adducts with large binding constants is demonstrated. For α,ω-aliphatic diamines, binding constants progressively increase with the increasing length of the alkyl chain, thanks to the flexible nature of the spacer and there is a parallel decrease of the conformational strain upon binding for longer diamines, reaching the largest value for the 1,8-diaminooctane. Stable adducts are also found even for short diamines with rigid molecular structures. The preorganized structure of these ditopic species which, except for the entropic cost upon binding the diamine to 1, are not subjected to loss of degrees of freedom, accounts for the large binding constants. These binding characteristics can be exploited for the detection of ditopic strong Lewis bases. The colorimetric and fluorometric selective and sensitive detection has been demonstrated for piperazine.

Author Contributions: All experimental work was performed by G.M., G.C. and S.F. Data analysis was performed by G.M., S.F. and S.D.B. The manuscript was written by S.D.B., with contributions from the other authors. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not Applicable. Acknowledgments: This work was supported by the University of Catania, PIACERI 2020/2022, Linea di Intervento 2. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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