This is the peer reviewed version of the following article: Mancebo-Aracil J., Casagualda C., Moreno-Villaécija M.Á., Nador F., García-Pardo J., Franconetti-García A., Busqué F., Alibés R., Esplandiu M.J., Ruiz-Molina D., Sedó-Vegara J.. Bioinspired Functional Catechol Derivatives through Simple Thiol Conjugate Addition. Chemistry - A European Journal, (2019). 25. : 12367 - . 10.1002/chem.201901914, which has been published in final form at https://dx.doi.org/10.1002/chem.201901914. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. FULL PAPER Bioinspired Functional Catechol Derivatives Through Simple Thiol Conjugate Addition Juan Mancebo-Aracil,*[a][b] Carolina Casagualda,[c] Miguel Ángel Moreno-Villaécija,[a] Fabiana Nador,[b] Javier García-Pardo,[a] Antonio Franconetti-García,[c] Félix Busqué,[c] Ramon Alibés,[c] María José Esplandiu,[a] Daniel Ruiz-Molina,[a] Josep Sedó-Vegara*[a] Abstract: The combination of the surface-adhesive properties of a successful design for catechol-capped functional coatings, catechol rings and functional moieties conveying specific properties based on the synthesis of catechol derivatives bearing a specific is very appealing to materials chemistry, but the preparation of functional moiety in the 4- position, followed by their catechol derivatives often requires elaborate synthetic routes to polymerization in an excess of hydroalcoholic ammonia. This circumvent the intrinsic reactivity of the catechol ring. In this work, design ensured both a robust (non-hydrolyzable) attachment of functional catechols are synthesized straightforwardly using the the functional moiety to the catechol ring, and an accurate bioinspired reaction of several functional thiols with o-benzoquinone. control of the degree of functionalization of the final material. With one exception, the conjugated addition of the thiol takes place Nevertheless, a relatively lengthy synthetic route was needed to regioselectively at the 3-position of the quinone, and is rationalized afford the respective catecholic derivatives, comprising by DFT calculations. Overall, this synthetic methodology is shown to protection/deprotection of the catechol ring, relatively harsh provide a general and straightforward access to functional and reaction conditions, and overall poor atom economy. These chain-extended catechol derivatives, which are later put to the test drawbacks limited the scope of application of this route, which with regard to their hydro/oleophobicity, colloidal stability, could not satisfy the need for a general approach to the fluorescence and metal-coordinating capabilities in proof-of-concept preparation of functional catechol derivatives. applications. Despite the growing interest for the synthesis of functionalized catechols, few other synthetic methodologies affording robust Introduction attachment of functional chains to simple catechols have been described in the literature. For example, the electrophilic aromatic substitution on catecholic derivatives using electrophile Biomimetic analogues of mussel-adhesive foot proteins (mfp’s) species allows the introduction of different alkyl and acyl have been the subject of intensive research over the past years. substituents on this ring, either in 3- or 4- position. However, in The remarkable ability of these marine organisms to cling, not most examples this methodology is only applied to specific only to rocky surfaces native to their environment, but virtually to cases yielding mixtures of 3- and 4- alkylated catechols,[7] or any surface (even low-fouling materials), has been largely mixtures of mono- and dialkylated products.[8] Examples where a attributed to the presence of a significant fraction of catecholic acylated[9] or single alkylated[10] catechol is obtained are scarce. amino acid L-3,4-dihydroxyphenylalanine (L-DOPA) in the On the other hand, the oxidation of a starting catechol to the sequence of the mfp’s.[1] Hence, an increasing number of works corresponding o-quinone and subsequent conjugated have focused on the synthesis of new bioinspired catechol- nucleophilic addition of a thiolated derivative should provide a based molecules and polymers, which have shown to be useful straightforward way to attach substituents of choice to catechol for manufacturing water-resistant adhesives,[2] protective rings via non-hydrolyzable S-aryl linkages. Indeed, the complex layers,[3] and primers for functional adlayers and nanoscale interplay between thiol groups and o-quinones is known to play coatings,[4] among others.[5] In a previous report,[6a] we presented important roles in biological contexts; for instance, it has been invoked as a repair mechanism in mussel foot proteins, where catechol moieties in L-DOPA units undergo oxidation in their [a] J. Mancebo-Aracil, J. Sedó-Vegara, M. A. Moreno-Villaécija, J. natural environment with a concomitant loss of the adhesive García-Pardo, María José Esplandiu, D. Ruiz-Molina capabilities. In the presence of free thiols of cysteine units in the Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST protein sequence, redox exchanges, as well as conjugate Campus de la UAB - 08193 Bellaterra (Spain) addition reactions restore the structure of the catechol ring, while E-mail: josep.sedo@icn2.cat at the same time increasing the bulk cross-linking density.[11] [b] J. Mancebo-Aracil, F. Nador Other relevant examples are evinced by the biosynthesis of Instituto de Química del Sur-INQUISUR (UNS-CONICET) Universidad Nacional del Sur pheomelanin and the neutralization of o-quinoid species derived Av. Alem 1253, 8000 Bahía Blanca, Buenos Aires (Argentina) from catechol estrogens by conjugation with cysteine free thiols, E-mail: juan.mancebo@uns.edu.ar which is thought to be the main mechanism behind the [c] C. Casagualda, A. Franconetti-García, F. Busqué, R. Alibés protective role of this amino acid against highly electrophilic Departament de Química Universitat Autònoma de Barcelona (UAB) carcinogenic metabolites.[12] So far, thiol-quinone conjugation for Campus de la UAB - 08193 Bellaterra (Spain) synthetic purposes has been shown for cysteine units, thiophenol, mercaptobenzothiazole and ethanethiol to different Supporting information for this article is given via a link at the end of catechol derivatives,[13],[14], but to the best of our knowledge, no the document. general approach for the preparation of simple catechol S- FULL PAPER functional derivatives for potential applications in materials amounts of 1a-disulfide suggested that at least a certain amount science has been reported. of unreacted thiol 1a also participates of redox-type side- reactions with o-quinoid species (Scheme 1). An overall picture of this seemingly simple reaction may be thus laid out, in which Here we report a systematic and straightforward methodology at least seven different species are coupled together by for the synthesis of functional catechol derivatives by oxidation conjugate nucleophilic additions and redox exchanges (SM, of the simplest catechol (pyrocatechol) to the corresponding o- Figure S1). In the former, o-quinones act as electrophilic quinone, followed by the conjugated nucleophilic addition of counterparts for the nucleophilic thiol, whereas in the latter, the different thiol-capped reagents bearing functional substituents. thiol reagent, and both pyrocatechol and thiolated catechols, act Thiolated precursors were chosen for several reasons: they are as reducing agents for both o-benzoquinone and thiolated o- widely available, they may be used either as simple functional quinones. Further support for this hypothesis was gained from moieties themselves or as chain-extenders, they provide robust non-aqueous cyclic voltammetry experiments on pyrocatechol aryl-S links to the pyrocatechol ring and, last but not least, and mono-adduct 2a, showing peak oxidation potentials at ca. optimal atom efficiency. Following this procedure, a wide variety +1.4 V vs Ag/Ag+ for both catecholic species (Fig. S5), With of moieties, such as aliphatic, fluorinated, polyethylene glycol- regard to regioselectivity, it was observed that the conjugated bearing (PEGylated) chains, fluorescent tags and chain addition of 1a took place essentially at the 3-position, since no extenders, are introduced in the catecholic ring using a unified traces of the 4-substituted derivative could be detected in the methodology. In order to showcase the usefulness of these reaction crude. This result is consistent with previous reports on catecol derivatives we present their use as coatings for the the selectivity of conjugated addition of thiol derivatives to modification of the wettability of macroscopic surfaces, the different oxidized catechol derivatives. [16] stabilization of colloidal dispersions of nanoparticles in aqueous In order to improve the conversion of the addition reaction solutions, and the preparation of coordination ligands that serve towards the mono-adduct 2a, several changes in the reaction as fluorescent markers for theranostic nanoparticles in conditions were screened (Table 1, entries 2-14), and the biomedical applications. progress of the reaction was followed by 1H NMR spectroscopy of the reaction crude. Replacement of CH2Cl2 by other solvents led to lower conversion values of thiol 1a (entries 2 & 3). Results and Discussion Changes in the reaction temperature turned out to be detrimental to net conversion into 2a (entries 4 & 5). The The attachment of thiolated chains to pyrocatechol takes place introduction of activators in the reaction mixture, either basic in in two stages. Pyrocatechol is first oxidized to o-benzoquinone. order to increase the nucleophilic character of the tiol, or acidic A thiol is subsequently added, undergoing nucleophilic attack to in order to enhance the electrophilicity of the quinone system, the quinoid ring. The reaction proceeds through a keto-enol were generally detrimental to the course of the reaction (1,8- intermediate that spontaneously tautomerizes into the Diazabicyclo[5.4.0]undec-7-ene (DBU), bis(trifluoromethane) substituted catecholic form (Scheme 1, top). sulfonamide (TFSI) or Ti(BuO)4), or neutral at best (L-Proline), compared to activator-free reaction conditions (entries 6-9). The Optimization of the reaction. The thiol of choice for the study only exception was trifluoroacetic acid (TFA, entries 10-14), and optimization of the conjugate addition reaction was 1- which was observed to enhance significantly the overall octadecylthiol 1a. The oxidation of pyrocatechol to the conversion of the thiol, as well as the production of the desired corresponding o-benzoquinone was carried out in water using a mono-adduct 2a, already when the activator was present in sub- small excess of one equivalent of NaIO4,[15] commonly used for stoichiometric amounts. A favorable trend was observed by the oxidative activation and cross-linking of catechol-based increasing the amount of TFA up to 3 eq (entry 12), which adhesives. Although the oxidation step proved to be yielded a high overall conversion of the thiol (ca. 80%), and the reproducible with yields of pure o-benzoquinone around 75%, highest mono-adduct content in the reaction mixture (>4:1 molar the instability of this compound prompted us to skip the isolation ratio), with higher activator loadings offering no significant of the quinone altogether by extracting it into CH2Cl2, followed by advantage (entry 13). The use of a sub-stoichiometric amount of the immediate addition of one equivalent of the thiol under argon. the thiol (0.75 eq) led to the highest overall conversion of thiol 1a, In line with two previous reports,[13c,f] a mixture of the desired but the reaction mixture showed a lesser content in mono- mono-adduct 2a, together with a significant amounts of the adduct 2a (entry 14). symmetrical bis-adduct 3a and 1a-disulfide were detected in the 1 H NMR spectrum of the reaction crude, with the molar ratio between 2a and the sum of these two side-products being 1.1:1 (Table 1, entry 1). From a mechanistic point of view, the introduction of a second thiolated unit may be explained by assuming that a fraction of thiolated catechol 2a is oxidized by unreacted o-benzoquinone to the corresponding thiolated o- quinone, which then becomes the substrate for a second conjugate addition. The concomitant production of significant FULL PAPER Overall, the use of 3 eq of TFA in CH2Cl2 at room temperature offered the best balance between thiol conversion and mono- adduct purity (Table 1, entry 12). The suitability of these optimized conditions was confirmed with the isolation of mono- adduct 2a after purification by column chromatography in 61% yield, which could be separated successfully from a lesser amount of bis-adduct 3a (25%). Scope of the reaction. The optimal reaction conditions for the model reaction (room temperature, 3 eq of TFA), were used for the conjugation of several thiol compounds (1a-e, Table 2), chosen to bear functional moieties of interest to materials chemistry. Together with the long alkyl thiol previously discussed Scheme 1. Proposed mechanism for the obtention of mono- and bis-adducts (1a), a fluorinated (1b) and a PEGylated thiol (1c) were chosen of 1-octadecylthiol and pyrocatechol by combination of conjugate addition and redox reactions. for their potential ability to tune surface wettability and, in the latter case, in order to confer stability to nanoparticles in physiological media. On the other hand, mercaptobenzothiazole (1d) and a mercaptocoumarine (1e) were picked up to exemplify Table 1. Screening and optimization of the reaction conditions for octadecylthiol 1a[a] the coupling of thiolated heterocycles to catechol moieties. Table 2. Synthesis of functional catechols. Functional thiol Catechol derivative[a] En Solvent[a] Activator 1a 2a[e] Molar ratio[e] try conv (%) 2a:(3a + 1a- 1a [e][f] disulfide) (%) 2a, 61% 3a, 25% 1 CH2Cl2 - 65 15 1.1:1 2 n-hexane - 80 15 0.4:1 3 n-hexane/ - 55 15 0.7:1 1b 2b, 37% 3b, 16% CH2Cl2 (5:1) 4 CH2Cl2[b] - 70 15 0.6:1 5 CH2Cl2[c] TFA, 1 eq 75 20 0.8:1 1c 6 CH2Cl2 DBU, 0.1 eq - - - 2c, 56% 7 CH2Cl2 Ti(BuO)4, 1 - - - eq 8 CH2Cl2 TFSI, 1 eq - - - 1d 2d, 64% 9 CH2Cl2 L-Pro, 1 eq 65 20 0.8:1 10 CH2Cl2 TFA, 0.2 eq 75 30 1.4:1 11 CH2Cl2 TFA, 1 eq 85 40 2.0:1 12 CH2Cl2 TFA, 3 eq 80 55 4.3:1 1e 13 CH2Cl2 TFA, 5 eq 80 50 3.3:1 2e, 45% 14 CH2Cl2[d] TFA, 3 eq >95 55 2.7:1 [a] Yields referred to respective parent thiols after purification by column chromatography [a] General reaction conditions: 6h, room temperature, 1 eq of thiol 1a (except where otherwise stated); [b] 0ºC; [c] reflux; [d] 0.75 eq 1a; [e] Determined by 1H NMR of the crude material; values referred to thiol The expected mono-adducts 2a-e were thus obtained in 1a; [f] 2a + 3a + 1a-disulfide moderate to high yields (37-64%). In the case of alkyl and FULL PAPER fluoroalkyl derivatives 2a and 2b, the corresponding bis-adducts 3a and 3b were isolated alongside as by-products of the Table 3. Synthesis of chain-extended catechol-thiols, bis-catechols and synthesis, whereas in the other cases, only the intended mono- protected intermediates adducts (2c-e) could be purified from the reaction crude, and no traces from bis-adducts were observed. Overall, these results ,-dithiol Chain-extended catechol derivative [a][b] confirm that the optimized procedure may be generalized to obtain a wide variety of functional catecholic derivatives. With regard to the regioselectivity of the conjugate addition, and in agreement with a reported precedent using a different methodology,[14b] 2-mercaptobenzothiazole 1d was the only thiol 5a, 33% undergoing selective 1,4-addition to the 4- position, instead of the 1,6-addition to the 3- position of the ring observed for all the 4a other thiols tested. Remarkably, this regioselectivity was observed to be extensive to the second conjugate addition, which was observed to take place selectively at the 6- position for compounds 3a and 3b. 6a, 11% The next step in this study was the conjugation of one or two pyrocatechol molecules to ,-dithiols 4a-d bearing apolar alkyl chains (1,6-butanedithiol 4a and 1,6-hexanedithiol 4b), a polar moiety (2,2-(ethylenedioxy)diethanethiol) 4c), and pendant hydroxyl groups (DL-dithiothreitol 4d), in order to obtain catechol-thiol derivatives 5 and bis-catechol derivatives 6 (Table 5b, 35% (43%) 3). In both families of compounds, the central chain was 4b intended as a chain-extender in the catechol derivative, providing an adequate degree of flexibility, as well as enough spatial separation when needed, between the catechol moiety and either a second catechol moiety 6, or a free thiol 5. In the first case, bis-catechols 6 could be used as flexible bidentate ligands for coordination chemistry. In this regard, similar bis- 6b, 36% catechol molecules have been used successfully by our group as ligands for the preparation of coordination polymer particles, as well as polydopamine-like gatekeeping coatings.[17] With regard to catechol-thiols 5, the terminal thiol should allow further conjugation of the catechol-thiol to functional moieties bearing electrophilic reactive ends, such as vinyl, acrylate or isocyanate 5c, 35% (41%) groups, thus providing an straightforward alternative route to functional catechols. 4c Using a pyrocatechol/dithiol 1:1 molar ratio, catechol-thiols 5a-d were thus prepared by direct conjugation (Method A, see Experimental Section) in moderated yields ca. 35% (Table 3). Bis-catechol adducts 6a-6c were also isolated from the reaction crude in low-to-moderate yields (11-36%). For cases for which the separation of 5/6 mixtures should turn out problematic, an 6c, 11% alternative route (Method B) to catechol-thiols (5), comprising the selective protection and deprotection of a single thiol group, was also tested and exemplified for ,-dithiols 4b and 4c (Scheme 2, right). We first prepared and purified the corresponding monoacetylated thiols (7b and 7c), and subsequently conjugated them to o-benzoquinone in order to 4d 5d, 33% obtain the respective chain-extended catechol thioacetates (8b and 8c). Deprotection of these precursors in hydrochloric [a] Yields referred to respective parent thiols after purification by column acid/methanol proceeded quantitatively, affording the pure chromatography; [b] Yields reported for 5a-d (Method A), and 5b-c (Method B, between parentheses) catechol-thiols (5b and 5c) in final overall yields that were slightly higher (41-43%) than those of the direct route. FULL PAPER To show the feasibility of the functionalization of catechol-thiols thiols proceeded selectively in the presence of catechol rings, (5) by conjugation of the free thiol with electrophilic moieties, two without the need of any additional protection/deprotection steps. derivatives of compound 5b were prepared. Firstly, this Secondly, 5b was derivatized in moderate yield (60%) into the compound was selectively oxidized to the corresponding bis- corresponding fluorescent catechol derivative 10 by reaction catechol disulfide 9 with an equivalent of iodine (Scheme 3, left), with fluorescein 5(6)-isothiocyanate (FITC), a fluorescent marker in quantitative yield. It should be noted that, in contradistinction commonly used in biomedical applications (Scheme 3, right). As to the bis-catechol compounds 6 mentioned before, bis-catechol in previous steps, the atom efficiency of the reactions to prepare derivatives such as 9 include a central disulfide bridge, which is derivatives 9 and 10 is optimal. potentially cleavable. Remarkably, this oxidative coupling of Scheme 2. Synthesis of chain-extended catechol derivatives (5, 6) from ,-dithiols by direct conjugation (Method A), or conjugation sandwiched by selective protection/deprotection of one thiol group (Method B). Scheme 3. Synthesis of bis-catechol disulfide 9 and chain-extended fluorescein derivative 10. Computational studies. In order to rationalize the origin of the the largest coefficient of the LUMO orbital is located at the C-4 observed regioselectivity of the conjugate addition, theoretical position.[18a] In our particular system, the C-4 carbon of o- calculations were carried out at the PBE0-D3/def2-TZVP level of benzoquinone also presented the largest coefficient. Moreover, theory (see the experimental part for computational details). In molecular electrostatic potential (MEP) surface analysis of o- general, the 1,6-conjugated additions are not favored because benzoquinone (Fig. 1) revealed a positively charged region on FULL PAPER the surface of both C-3 and C-4 carbons, with electrostatic the structure and energy of transition states seems key to potential values at van der Waals distances favoring the C-4 explaining the observed differences in regioselectivity. position (7.6 vs 15.0 kcal/(mol·e) for C-3 and C-4, respectively). In view of these considerations, the addition of the thiol derivative should be expected at C-4 position as a general rule. (b) However, since with the exception of mono-adduct 1d, TS1a-C4 experimental results for all the other functional thiols showed 18.4 1.87 TS1a-C3 TS1a-C3 addition taking place instead at C-3, a more elaborate TSHB-C3 12.1 explanation was sought from calculations taking into account 2.43 different feasible reaction pathways. 0.0 Taking a model compound (ethanethiol) as a model for 1a, (a) TS1a-C4 results suggested that the attack on the C-3 position is favored +7.6 due to the incipient formation of a hydrogen bonding interaction between the thiol and one of the carbonyl groups of o- 2.37 benzoquinone. In this regard, a non-covalent C=O···H-S contact +15.0 ‒42.1 Pre-TSHB 2a-C4 was evinced both by atoms-in-molecules analysis (AIM, Fig. 1, ‒44.3 2a left) and the non-covalent interaction plot (NCI, Fig. S2). Eventually, this interaction leads to the formation of a bond path Figure 1. AIM analysis of bond critical points and paths showing hydrogen interconnecting the S atom with both the carbonyl and the C-3 bonding interactions in the early stages of the reaction (left). MEP of o- position (TSHB-C3). It seems thus reasonable to assume that this benzoquinone plotted on the van der Waals surface, with energies of C-3 and C-4 carbons (center, bottom). Calculated energy profile and optimized TS network of interactions helps anchor the thiol group in the close structures for the non-activated addition of an aliphatic thiol to o-quinone at C- vicinity of one of the carbonyl groups in early stages of the 3 (dashed blue lines) and C-4 (dark red lines) positions, optimized at the reaction, and thus drive the nucleophilic addition to the C-3 PBE0-D3/def2-TZVP level. All energy values are relative to the reactants and position. are given in kcal/mol; distances given in Å. Since regioselectivity on C-3 for 1a was observed experimentally both in the absence of activators and in the presence of TFA, we estimated the energy profiles in both cases. Taking into account that o-benzoquinone is able to form parallel-displaced -dimers (Ebind = -5.5 kcal/mol), a second quinone molecule was incorporated in the calculations for the non-activated reaction. For TS1a-C4, this was necessary for the capture of the thiol proton. In these systems, an increase in the LUMO coefficient at C-3 further favored the 1,6 addition (E = -6.3 kcal/mol). With regard to TFA-assisted transition states (TS1a-C3TFA and TS1a- C4TFA, Fig. S4), this activator facilitates the protonation of a carbonyl group, with the concomitant formation of a network of hydrogen bond-mediated interactions in both cases, favoring again the 1,6 addition (E = -5.8 kcal/mol). The calculated energy for the final C-3 (2a) and C-4 (2a-C4) adducts was roughly very similar. With regard to mercaptobenzothiazole 1d, it has already been reported that this molecule exists essentially in the keto form Figure 2. PBE0-D3/def2-TZVP optimized structures and energy profile for the addition of benzthiazoline-2-thione to o-quinone at C-3 (dashed blue lines) and (benzothiazoline-2-thione) in solution over a broad range of C-4 (dark red lines) positions. Energies are given in kcal/mol and distances in temperatures.[18b] Using our own calculation methodology, we Å. Hydrogen bonds in structures are highlighted by blue dashed lines. evaluated the relative stability of both benzothiazoline-2-thione (thioketo-1d) and 2-mercaptobenzothiazole (thioenol-1d) tautomers. In agreement with the previous study, thioketo-1d Proof-of-concept examples. In order to show the potential was indeed predicted to be the most stable tautomer (-11.2 usefulness of the functional catechols reported here, some of kcal/mol) in CH2Cl2, so we picked up this species for all energy them were put to test as functional coatings for macro- and profile calculations (Fig. 2). nanostructures and functional ligands for bioapplications. Similarly to transition states for 1a, TFA was shown to assist in First, alkylated mono- and bis-adducts 2a and 3a, polyfluoroalkyl the protonation of carbonyl groups and the establishment of homologues 2b and 3b, as well as polymers p2a and p2b complex networks of hydrogen bonds (this time around involving derived from the aerobic oxidation products of 2a and 2b, were with the nitrogen-bound proton), but TS1d-C4TFA ended up being used to prepare hydro- and oleophobic coatings for macroscopic significantly favored compared to TS1d-C3TFA (E = -11.8 surfaces. From a structural point of view, it may be noted that kcal/mol). As with alkyl adducts, calculated energy differences the alkylated S-catechol mono-adduct (2a) is very similar to between final regioisomers 2d and 2d-C3 are minimal, so overall urushiol-type alkylcatechols, which are the main components of FULL PAPER traditional Japanese lacquered coatings. [19] For the preparation of TiO2 p2a and p2b, we followed a procedure recently reported by us for the oxidative polymerization of 4-heptadecylcatechol.[5] Briefly, blank isopropanol solutions of each mono-adduct were mixed with an excess of aqueous ammonia and stirred in air at room temperature, yielding dark-brown precipitates that were 2 3 p2 extracted in apolar solvents, and further deposited on substrates by dip coating. Although the exact chemical composition of a ammonia-oxidized catechol derivatives was not determined,[5] they are likely formed in a similar way to polydopamine and other melanin-like materials in general.[6] Presumably, after the oxidation of catechol moieties by atmospheric oxygen in moderately basic media, the corresponding o-quinone and b semiquinone intermediates either couple directly, or through ammonia, which would act as a nucleophile on the reactive o- quinones thus formed, either through Michael addition or by direct attack on a quinoid carbonyl to form a Schiff base.[5] Cotton cloth Regardless of the exact mechanism/s involved, because of the many potentially reactive positions involved, any combination of these reactions would be expected to eventually provide a p2a certain degree of covalent linkage between catechol moieties, thus giving rise to a mixture of oligomeric/polymeric species bearing functional (in this particular case, hydrophobic) substituents. TiO2 surfaces and cotton cloth were dip-coated with solutions of p2b alkyl (2a, 3a) and polyfluoroalkyl (2b, 3b) derivatives, as well as that of polymerized mono-adducts (p2a, p2b), and the corresponding static contact angles (SCA) were measured. For water tetradecane TiO2 (Figure 3, top), results for water drops are virtually identical to each other, proving that all long-alkyl and Figure 3. Static contact angles (SCA) of water drops on TiO2 surfaces polyfluoroalkylcatechols monomers and polymers reported here Uncoated TiO2 blank; TiO2 coated with alkylcatechol derivatives 2a, 3a and p2a, and polyfluoroalkyl catechol derivatives 2b, 3b and p2b. SCA of fluid confer hydrophobicity to this metal oxide surface. Significant drops on coated cotton coated with alkylated polymer p2a (water) and differences arose, however, after testing coated cotton samples. polyfluoroalkylated polymer p2b (water, tetradecane). For non-polymeric catechol derivatives (2a, 3a, 2b and 3b) no contact angle could be measured due fast water absorption by the textile. However, impregnation of cotton with p2a and p2b afforded hydrophobic coatings with high contact angle for water droplets (Figure 3, bottom). Particularly, the water CA of p2a- coated cotton (150º) turned out to be qualitatively similar to that reported by us for ammonia-polymerized 4-heptadecylcatechol (134º),[5b] and comparatively persistent. Moreover, for the polymerized polyfluorinated derivative p2b, the lack of wetting of the treated surface by tetradecane (CA = 130º) shows that this material is able to confer strong oleophobicity to the otherwise highly absorbent and hydrophilic cotton. The ability of S-catechol derivatives to coat nanostructures was shown in a first example by polymerizing bis-catechol disulfide 9, following an in situ protocol previously reported for the melanization of other bis-catechols intended as “plug” coatings for nanocarriers.[17b] Mesoporous silica nanoparticles (MSNs) were then suspended in a solution of polymer p9 to carry out the deposition of the coating. Scanning transmission electron microscopy (STEM) images showed silica cores surrounded by a thick layer (ca. 200 nm) of the catecholic polymer, which was evinced in the energy-dispersive X-ray spectroscopy (EDX) line FULL PAPER scan by the presence of a significant amount of sulfur across the in a water/n-hexane mixture. Whereas a control of the original whole diameter of a coated particle, in contradistinction to the Si NPs remained dispersed in the organic phase of the mixture signal, which appeared circumscribed to its inner section, i.e. to after vigorous shaking, 2c-coated NPs were readily transferred the mineral core (Figure 4). to the aqueous phase (Figure 5). This change in the wettability behavior is explained by the hydrophilic PEGylated derivative 2c replacing the original (hydrophobic) oleic acid layer on the NPs. The comparatively higher affinity of catechol moieties for iron atoms is thought to be instrumental in this ligand displacement. Finally, we tested the fluorescein-grafted derivative 10 as a fluorescent marker/ligand for the design of new theranostic nanocarriers. Firstly, coordination polymer nanoparticles (CPNPs) were prepared by using a previously reported generic protocol based on the fast-precipitation method.[17a] For this work, a b 200 nm a CoII salt was reacted with a combination of a bidentate scaffold 200 nm ligand (1,4-bis(imidazol-1-ylmethyl)benzene (BIX)),[20] and two catechol derivatives - a catecholic prodrug moiety (L-DOPA c d Si methyl ester), and 10 -, both acting as monodentate ligands S filling up the remainder of the metal coordination sphere (Scheme 4). 10-containing nanoparticles of ca. 50 nm in diameter readily precipitated from the reaction crude. As evinced by their fluorescence emission spectrum (Figure 6, top), the marking capabilities of the parent fluorescent moiety were 0 200 400 600 800 1000 500 nm d (nm) preserved after its incorporation in the coordination polymer. In order to test these properties in a bioassay, M17 neuroblastoma Figure 4. a) SEM image of uncoated mesoporous silica nanoparticles (MSNs); cells were incubated at 37 °C in the presence of 10-marked b) TEM image of a coated MSN singled out for EDX line scan, with arrows CPNPs (50 µg/mL) for 6 hours. The in vitro internalization of the indicate the approximate edges of the coating; c) TEM image of MSNs coated fluorescent nanoparticles was followed by confocal fluorescence with p9; d) EDX line scan profile. microscopy, and their intracellular localization was checked by means of 3D image reconstructions (Figure 6, bottom), showing clusters of nanoparticles (green) located inside the cell cytoplasm, but outside the nucleus (blue) and lysosomes (red). This experiment qualitatively demonstrated both the stability and the successful uptake of 10-marked CPNPs in physiological FexOy FexOy environments, hinting at the potential of functional chain- extended catechol-based compounds (10) as auxiliary ligands for the design of multifunctional nanocarriers for biomedical applications. Oleic acid OA 2c Hexane Hexane (FexOy@OA) Water Water (FexOy@2c) Figure 5. Stabilization of a colloidal dispersion of FexOy NPs in a n- hexane/water mixture as originally coated with oleic acid (left) and after treatment with PEGylated derivative 2c. In a second example, the colloidal stabilization capabilities of PEGylated catechol 2c were explored by treating a n-hexane suspension of oleic acid-stabilized iron oxide nanoparticles Scheme 4. Synthesis of 10-marked fluorescent coordination polymer (NPs) with a dichloromethane solution of this catechol derivative. nanoparticles. After centrifugation, iron oxide nanoparticles were re-suspended FULL PAPER which was rationalized by means of theoretical DFT calculations a Fluorescence (a.u.) Absorbance (a.u.) taking into account feasible reaction pathways. In order to showcase the potential usefulness of S-catecol compounds for surface energy modification, alkyl, fluoroalkyl and PEGylated derivatives thus prepared were successfully incorporated as coatings to tune the wettability of macroscopic surfaces and the dispersability of nanoparticles. Furthermore, a chain-extended catechol bearing a fluorescent tag was used as a ligand to build a new theranostic coordination-polymer-based nanocarrier, which showed satisfactory in vitro cell b internalization and biomarking capabilities. Overall, the catechol derivatives reported here should be of general interest to materials chemistry, as well as for biomedical applications requiring adequate stabilization and internalization of nanostructured theranostic agents. c Experimental Section Materials and Methods. All reagents were purchased from Sigma- Aldrich and used as received. Synthesis-grade solvents were purchased from Scharlab, S.L. and used without further purification. Opti-MEM medium, fetal bovine serum and commercial fluorescent dyes were purchased from Thermo Fischer Scientific. Human BE(2)-M17 cells were obtained from the American Type Culture Collection (ATCC). 1,4- bis(imidazol-1-ylmethyl)benzene was synthesized following a reported procedure.[21] Oleic acid-stabilized iron oxide nanoparticles were prepared according to a reported procedure.[22] Fourier transform infrared spectroscopy (FT-IR) was carried out on a Thermo Nicolet Nexus equipped with a Goldengate attenuated total Figure 6. a) Size distribution (SEM) and fluorescence response (excitation, reflectance (ATR) device (neat samples), or on a Bruker Tensor 27 FT-IR red line; emission, blue line) of 10-marked CPNPs; b) Confocal fluorescence microscopy images of dopaminergic human neuroblastoma (BE)2-M17 cells spectrometer (KBr pellets). NMR spectra were recorded on Bruker cultured in vivo with 10-marked CPNPs showing accumulated CPNPs inside DPX250, DPX360 and ARX400 spectrometers. ESI-MS was carried out cells (green). Cell membranes stained with cell mask (grey), cell nuclei with in negative mode on an Agilent 6545 Q-TOF mass spectrometer. Cyclic Hoechst staining (blue); and liposomes with LysoTracker® Red; c) 3D voltammetry (CV) experiments were run on a CHI 660D Electrochemical reconstructed image of a single cell. Station (CHI Instruments), using a non-aqueous Ag/Ag+ reference electrode containing 10 mM of AgNO3, a Pt wire as counterelectrode and a glassy carbon working electrode (surface area: 4.71 mm2). Scanning Conclusions electron microscopy (SEM) and scanning transmission electron microscopy (STEM) images were acquired on a FEI Magellan 400L in extreme resolution mode (XHR) at 20 kV, using a carbon coated copper grid as support. Scanning-transmission electron microscopy (STEM) A versatile and unified methodology to prepare functional images and energy dispersive X-ray (EDX) line scan profiles were catechol derivatives with optimal carbon atom efficiency and obtained at room temperature and 200 kV on a FEI Tecnai G2 F20 robust attachment of the functional moiety has been investigated coupled to an EDAX detector. UV/Vis spectra were recorded on a Cary by means of a conjugate addition reaction of functional thiols to 4000 spectrophotometer (Agilent). Fluorescence emission was measured freshly prepared o-benzoquinone from simple pyrocatechol, on a Hitachi F-2500 fluorescence spectrophotometer with excitation and using a straightforward protocol. This synthetic strategy is emission slits of 5 nm and a photomultiplier tube (PMT) voltage of 400 V. Optical and fluorescence images were recorded on a Zeiss Axio reminiscent of mechanisms found in nature –such as the repair- Observer Z-1 inverted optical/fluorescence microscope with a motorized and-crosslink role of thiolated moieties responsible for the XY stage, Hg-lamp excitation source, AxioCam HRc digital camera, and restoration of the catecholic function in mussel foot proteins-, standard filters, and in fluorescence mode with an Alexa Fluor 546 filter. and we have shown that it may be readily co-opted to gain Cells were imaged in vivo in a Leica TCS SP5 confocal fluorescence access to a wide scope of functional catechol derivatives microscope at 37°C. Image analysis and 3D reconstruction was carried incorporating aliphatic, fluorinated, PEGylated chains, or out with Bitplane Imaris software. fluorescent tags, among other functional units, as well as to chain extensions. In most cases, the conjugated addition of the Geometry optimizations were carried out with the hybrid PBE0 functional[23] at the def2-TZVP level of theory.[24] In addition, the Grimme’s thiol proceeds regioselectively at the 3-position of the quinone, dispersion correction[25a] was also included as implemented in Turbomole 7.0[25b]. In order to characterize the nature (minimum or transition state) FULL PAPER of optimized structures, the analysis of the corresponding frequencies 4H), 1.43-1.23 (m, 60H), 0.91-0.86- (m, 6H); 13C NMR (90 MHz, CDCl3) was conducted at the same level of theory. Thus, minima are described δ: 143.8, 124.9, 121.0, 35.7, 32.1, 29.8, 29.8, 29.7, 29.7, 29.6, 29.5, 29.3, by the absence of negative eigenvalues (imaginary frequencies, Nimag = 28.8, 22.8, 14.3; HRMS (ESI) m/z calculated for C42H79O2S2 [M + H]+: 0) whereas transition states (TS) present one imaginary frequency (Nimag 679.5521; found 679.5363. = 1) in all cases. Implicit solvent effects (CH2Cl2) were considered during the optimization by applying the polarizable continuum model (PCM) with 3-((1H,1H,2H,2H-perfluorodecyl)thio)benzene-1,2-diol 2b and 3,6- the integral equation formalism variant (IEFPCM)[26] by means of a single bis((1H,1H,2H,2H-perfluorodecyl)thio)benzene-1,2-diol 3b. The point calculations at the same level of theory using the Gaussian 16 reaction mixture was purified by column chromatography with 7/3 package.[27] Representative models were selected for each reaction as hexane/ethyl acetate, yielding 218 mg (37%) of mono-adduct 2b and 85 trade-offs between accuracy and computational cost. The molecular mg (16%) of bis-adduct 3b. 2b: Yellowish solid; IR (neat): max 3447, electrostatic potential (MEP) surface of o-benzoquinone (isosurface, 2959, 2924, 2854, 1608, 1587, 1488, 1464, 1342, 1240, 1208, 1146 0.001 a.u.) was also computed at PBE0-D3/def2-TZVP level of theory to cm−1;1H NMR (360 MHz, CDCl3) δ: 7.01 (dd, J = 7.9, 1.5 Hz, 1H), 6.97 study differences of electrophilicity in carbon atoms. In addition, the “non- (dd, J = 8.1, 1.5 Hz, 1H), 6.83 (dd, J = 8.1, 7.9 Hz, 1H), 2.95 (m, 2H), covalent interaction plot” (NCIplot) isosurfaces[28a] were also computed 2.34 (m, 2H), ArOH n.d.; 13C NMR (90 MHz, CDCl3) δ: 144.8, 144.6, with the aim to confirm the additional hydrogen bonding interaction found 126.8, 125.6, 121.6, 117.4, 30.1, 27.1; elemental analysis calculated for in these structures. The colour codes (red-yellow-green-blue) of surfaces C16H9F17O2S: C, 32.67; H, 1.54; S, 5.45%; found: C, 32.65; H, 1.57; S, in this schematic representation are red for ρcut+ (repulsive) and blue for 5.40%. 3b: White solid; IR (neat): νmax 3392, 2948, 2851, 1596, 1444, ρcut- (attractive). “Atoms-in-molecules” theory[28b] has been implemented 1368, 1301, 1219, 1152 cm−1;1H NMR (360 MHz, CDCl3) δ: 6.98 (s, 2H), by means of the AIMall calculation package. [28c] 6.26 (br.s, 2H), 3.03 (m, 4H), 2.35 (m, 4H); 13C NMR (90 MHz, CDCl3) δ:144.6, 125.7, 119.8, 110.5, 32.1, 30.1, 26.0; elemental analysis Syntheis of o-benzoquinone. To a solution of 936 mg of NaIO4 (4.4 calculated for C26H12F34O2S2: C, 29.28; H, 1.13; S, 6.01%; found: C, mmol) in 150 mL of H2O cooled in an ice bath, a solution of 440 mg of 29.49; H, 1.15; S, 6.15%. pyrocatechol (4 mmol) in 5 mL of Et2O was added and left stirring vigorously for 15 min. The orange-reddish reaction mixture was extracted 3-(methoxy(polyethyleneoxy)ethylthio)benzene-1,2-diol 2c. The with 4x15 mL of CH2Cl2, and the organic phase concentrated to about 1/5 reaction mixture was purified by column chromatography with 8/2 to 5/5 of the original volume under reduced pressure. 15 mL of n-Hexane were gradient of hexane/ethyl acetate, yielding 286 mg (56%) of mono-adduct added to the concentrate and the mixture cooled down to -10°C. 2c. Pale yellow oil; IR (neat): max 3384, 2959, 2915, 2851, 1602, 1590, Crystallization yielded 265 mg of pure o-benzoquinone (61%) as deep 1470, 1251 cm−1;1H NMR (400 MHz, CDCl3) δ: 6.93 (dd, J = 7.8, 1.5 Hz, red needles. 1H NMR (360 MHz, CDCl3) δ: 7.05 (dd, J = 8.0, 3.6 Hz, 2H), 1H), 6.89 (dd, J = 8.0, 1.5 Hz, 1H), 6.66 (dd, J = 8.0, 7.8 Hz, 1H), 3.65- 6.41 (dd, J = 8.0, 3.6 Hz, 2H). 13C NMR (90 MHz, CDCl3) δ: 180.5, 139.5, 3.55 (m, >70H), 3.33 (s, 3H), 2.92 (t, J = 5.8 Hz, 2H), 2.90 (t, J = 5.8 Hz, 131.1. 2H), ArOH n.d.; 13C NMR (100 MHz, CDCl3) δ: 145.8, 145.2, 126.5, 120.5, 119.1, 116.7, 70.5, 69.1, 59.2, 36.0; HRMS (ESI) m/z calculated General procedure for the telescoped synthesis of functional for C47H92NO22S [M + NH4]+ 1054.5832; found 1054.5826; HRMS catecholic mono-adducts (2). For the preparation 2a-e, 1 mmol of the (MALDI) m/z calculated for C47H88NaO22S [M + Na]+ 1059.5386; found corresponding thiol (1a-e) was dissolved in 2 mL of CH2Cl2 in a Schlenk 1059.5522, both corresponding to n = 19, together with several satellite flask under nitrogen. To this, 229.5 μL of trifluoroacetic acid (TFA, 3 peaks corresponding to n around 20. mmol) were added with stirring. In a separate flask, a solution of 234 mg of NaIO4 (1.1 mmol) in 38 mL of H2O was prepared and cooled in an ice 4-(benzo[d]thiazol-2-ylthio)benzene-1,2-diol 2d. The reaction mixture bath. 110 mg of pyrocatechol (1 mmol) dissolved in 1 mL of Et 2O were was purified by column chromatography with 7/3 hexane/ethyl acetate, added to the aqueous solution and left stirring vigorously for 15 min. The yielding 175 mg (64%) of mono-adduct 1d. Orange solid; IR (neat): max orange-reddish o-benzoquinone was extracted with 4x8 mL of CH2Cl2, 3517, 3433, 3053, 2927, 2687, 2544, 1595, 1504, 1451, 1416, 1320, and the organic phase was dried over anhydrous Na2SO4, filtered and 1276, 1028 cm−1;1H NMR (360 MHz, CD3OD) δ: 7.76 (d, J = 7.5 Hz, 1H), immediately added to the thiol solution. The reaction mixture was stirred 7.73 (d, J = 7.4 Hz, 1H), 7.42 (dd, J = 7.7, 7.5 Hz, 1H), 7.28 (dd, J = 7.7, in the dark at room temperature under nitrogen for 6 h. After this, the 7.4 Hz, 1H) 7.17 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 8.1, 2.1 Hz, 1H), 6.93 solvent and the TFA were evaporated under reduced pressure and the (d, J = 8.1 Hz, 1H); 13C NMR (90 MHz, CD3OD) δ: 143.3, 142.9, 125.7, crude was purified by column chromatography. For 2c the same 119.9, 118.4, 115.3, 35.9, 31.1, 28.9, 28.8, 28.8, 28.7, 28.6, 28.5, 28.3, procedure was carried out at half the scale stated above for all 27.7, 21.8, 13.3; HRMS (ESI) m/z calculated for C13H9NNaO2S2 [M + ingredients and solvents. Yields are referred to the corresponding Na]+ 297.9972; found 297.9963. starting thiol, unless otherwise stated (see SI for details). 7-((2,3-dihydroxyphenyl)thio)-4-methyl-2H-chromen-2-one 2e. The 3-(octadecylthio)benzene-1,2-diol 2a and 3,6-bis(octadecylthio) reaction mixture was purified by column chromatography with 1/1 benzene-1,2-diol 3a. The reaction mixture was purified by column hexane/ethyl acetate, yielding 67 mg (45%) of mono-adduct 2e. Brownish chromatography with 9/1 hexane/ethyl acetate, yielding 242 mg (61%) of solid; IR (neat): max 3421, 3251, 2956, 2913, 2597, 2422, 1707, 1675, mono-adduct 2a and 85 mg (25%) of bis-adduct 3a. 2a: White solid; IR 1599, 1584, 1537, 1473 cm−1;1H NMR (360 MHz, (CD3)2SO) δ: 9.83 (br. (neat): max 3384, 2959, 2915, 2851, 1602, 1590, 1470, 1251 cm−1;1H s, 1H), 9.14 (br. s, 1H), 7.68 (d, J = 8.2, 1.6 Hz, 1H), 7.08 (d, J = 8.2 Hz, NMR (360 MHz, CDCl3) δ: 7.00 (dd, J = 8.0, 1.7 Hz, 1H), 6.91 (dd, J = 1H), 6.99 (dd, J = 7.9, 1.5 Hz, 1H), 6.91 (dd, J = 7.8, 1.5 Hz, 1H), 6.89 (d, 7.8, 1.7 Hz, 1H), 6.78 (dd, J = 8.0, 7.8 Hz, 1H), 6.59, 5.34, (2 x br. s, 2H), J = 1.6 Hz, 1H), 6.78 (dd, J = 7.9, 7.8 Hz, 1H), 6.33 (s, 1H), 2.41 (s, 3H); 2.71 (dd, J = 7.9, 7.0 Hz, 2H), 1.63-1.52 (m, 2H), 1.40-1.25 (m, 30H), 13 C NMR (90 MHz, (CD3)2SO) δ: 160.8, 154.4, 153.7, 146.3, 144.0, 126.9, 0.90-0.87 (m, 3H); 13C NMR (90 MHz, CDCl3) δ: 143.3, 142.9, 125.7, 126.5, 122.8, 120.8, 117.9, 117.4, 115.8, 113.4, 113.1, 18.7; elemental 119.9, 118.4, 115.3, 35.9, 31.1, 28.9, 28.8, 28.8, 28.7, 28.6, 28.5, 28.3, analysis calculated for C16H12O4S: C, 63.99; H, 4.03; S, 10.68%; found: C, 27.7, 21.8, 13.3; HRMS (ESI) m/z calculated for C24H42NaO2S [M + Na]+: 64.03; H, 4.01; S, 10.62%. 417.2803; found 417.2785. 3a: White solid; IR (neat): max 3538, 3386, 2918, 2851, 1600, 1475, 1440, 1297 cm−1;1H NMR (360 MHz, CDCl3) δ: Synthesis of chain-extended catechol-thiols (5) and bis-catechols 6.93 (s, 2H), 6.35 (br.s, 2H), 2.76 (dd, J = 7.5, 7.2 Hz, 4H), 1.52-1.66 (m, (6). FULL PAPER Method A: by direct reaction between o-benzoquinone and a dithiol (4) 2.50 (ddd, J = 7.5, 7.3, 7.3 Hz, 2H), 1.62-1.51 (m, 4H), 1.44-1.35 (m, 4H), The general procedure for the conjugate addition was followed, by 1.33 (t, J = 7.5, 1H); 13C NMR (100 MHz, CDCl3) δ: 144.4, 144.1, 126.9, employing 0.5 mmol or 1 mmol of dithiol (4a-d). Crudes were purified by 121.0, 119.4, 116.6, 36.8, 34.0, 29.8, 28.3, 28.1, 24.8; HRMS (ESI) m/z column chromatography. Yields are referred to the corresponding starting calculated for C12H19O2S2 [M + H]+: 259.0826; found 259.0678. 6b: Pale dithiol (4), unless otherwise stated (see SI for details). yellow oil; IR (neat): max 3458, 3180, 2926, 2546, 1570, 1390, 1190 cm−1; 1H NMR (400 MHz, CDCl3) δ: 6.98 (dd, J = 7.8, 1.6 Hz, 2H), 6.90 Method B: selective synthesis of catechol-thiols (5) from dithiols (4), (dd, J = 8.0, 1.6 Hz, 2H), 6.77 (dd, J = 8.0, 7.8 Hz, 2H), 4.92 (br.s, 4H), including protection/deprotection steps Synthesis of monoacetylated 2.68 (t, J = 7.3, 4H), 1.55-1.51 (m, 4H), 1.40-1.33 (m, 4H); 13C NMR dithiols (7). 3 mmol of dithiol (4b and 4c) were dissolved in 17 mL of (100 MHz, CDCl3) δ: 144.5, 144.2, 126.8, 121.0, 119.2, 116.7, 36.8, 29.7, CH2Cl2. To this, 17 mL of pyridine and 282 μL of acetic anhydride (2.5 28.3; elemental analysis calculated for C18H22O4S2: C, 58.99; H, 6.05; S, mmol) were added and stirred at room temperature for 16 hours. The 17.50%; found: C, 59.01; H, 6.04; S, 17.52%. solvent was removed under reduced pressure, and the residue repeatedly extracted with distilled water in order to remove the pyridine 3-((2-(2-(2-mercaptoethoxy)ethoxy)ethyl)thio)benzene-1,2-diol 5c completely, dried and evaporated under reduced pressure. Analysis of and 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis the 1H-NMR spectra of the washed crudes showed that 7b and 7c were (sulfanediyl))bis(benzene-1,2-diol) 6c. Using Method A, the reaction obtained approximately in 65% and 71% yields, respectively, mixed their mixture was purified by column chromatography with 7/3 of hexane/ethyl respective diacetylation side-products, as well as with very low amounts acetate, yielding 102 mg (35%) of catechol-thiol 5c, and 44 mg (11%) of (≤5% and ≤2%, respectively) of unreacted dithiols. Since the diacetylated bis-catechol 6c. Using Method B, the overall yield of 5c is 41%. 5c: Pale compounds do not participate in the subsequent conjugate addition and orange oil; IR (neat): max 3460, 3175, 2925, 2500, 1732, 1625, 1580, the starting dithiols were present in residual amounts, these crudes were 1315, 1201, 903 cm−1;1H NMR (400 MHz, CDCl3) δ: 7.59 (br. s, 1H), 6.99 used in the next step without further purification. Synthesis of catechol (dd, J = 7.8, 1.5 Hz, 1H), 6.92 (dd, J = 8.0, 1.5 Hz, 1H), 6.73 (dd, J = 8.0, thioacetates (8). The general procedure for the conjugate addition was 7.8 Hz, 1H), 5.79 (br. s, 1H), 3.69-3.66 (m, 4H), 3.64 (t, J = 6.4 Hz, 2H), followed, by using aliquots of the reaction crudes containing ca. 1 mmol 3.56 (t, J = 5.8 Hz, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.72 (dt, J = 8.2, 6.4 Hz, of the corresponding monoacetylated dithiol 7b or 7c (295 mg of crude 2H), 1.65 (t, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 145.7, 144.9, 7b and 315 mg of crude 7c for respective purities of 65% and 71%, 127.6, 120.9, 118.7, 116.8, 73.2, 70.4, 70.2, 69.0, 36.9, 24.6; HRMS according to the 1H-NMR spectrum). Crudes were purified by column (ESI) m/z calculated for C12H19O4S2 [M + H]+: 291.0725; found 291.0607. chromatography with 7/3 hexane/ethyl acetate, yielding of 133 mg (45%) 6c: Pale yellow oil; IR (neat): max 3445, 2935, 2510, 1617, 1548, 1196 of 8b and 138 mg (44%) of 8c. Synthesis of catechol-thiols (5). To a cm−1;1H NMR (400 MHz, CDCl3) δ: 7.65 (br.s, 2H), 7.01 (dd, J = 7.8, 1.5 solution of 150 mg of 8b or 166 mg of 8c in 10 mL of MeOH, 100 µL of Hz, 2H), 6.93 (dd, J = 8.0, 1.5 Hz, 2H), 6.76 (dd, J = 8.0, 7.8 Hz, 2H), concentrated HCl (37%) were added. The mixture was refluxed with 5.85 (br.s, 2H), 3.70 (s, 4H), 3.57 (t, J = 5.8 Hz, 2H), 2.94 (t, J = 5.8 Hz, stirring for 15 h. After this, the solvent was removed under reduced 2H); 13C NMR (100 MHz, CDCl3) δ: 145.8, 144.9, 127.8, 121.0, 118.7, pressure, 5 mL of distilled water were added and the organic fraction was 117.0, 70.2, 69.0, 37.0; elemental analysis calculated for C18H22O6S2: C, extracted with ethyl acetate (3x3 mL), dried over anhydrous Na2SO4 and 54.25; H, 5.56; S, 16.09%; found: C, 54.23; H, 5.53; S, 16.02%. filtered. The solvent was finally evaporated under reduced pressure, yielding 126 mg (98%) of 5b or 142 mg (98%) of 5c. 3-(((2R*,3R*)-2,3-dihydroxy-4-mercaptobutyl)thio)benzene-1,2-diol 5d. Using Method A, the reaction mixture was purified by column 3-((3-mercaptobuyl)thio)benzene-1,2-diol 5a and 3,3'-(butane-1,3- chromatography with 6/4 to 4/6 gradient of hexane/ethyl acetate, yielding diylbis(sulfanediyl))bis(benzene-1,2-diol) 6a. Using Method A, the 87 mg (33%) of catechol-thiol 5d. Pale yellow oil; IR (neat): max 3510, reaction mixture was purified by column chromatography with 8/2 of 3412, 2925, 2901, 1325, 1230, 1181cm−1; 1H NMR (400 MHz, CD3OD) δ: hexane/ethyl acetate, yielding 76 mg (33%) of catechol-thiol 5a, and 37 6.90 (dd, J = 7.7, 1.6 Hz, 1H), 6.74 (dd, J = 7.9, 1.6 Hz, 1H), 6.64 (dd, J = mg (11%) of bis-catechol 6a. 5a: Pale yellow oil; IR (neat): max 3450, 7.9, 7.7 Hz, 1H), 3.71 (ddd, J = 7.6, 5.5, 2.7 Hz, 1H), 3.66 (dt, J = 6.5, 2.7 2928, 2901, 2540, 1584, 1453, 1326, 1198, 902 cm−1;1H NMR (360 MHz, Hz, 1H), 3.03 (dd, J = 13.4, 5.5 Hz, 1H), 2.91 (dd, J = 13.4, 7.6 Hz, 1H), CDCl3) δ: 6.99 (dd, J = 7.7, 1.3 Hz, 1H), 6.91 (dd, J = 8.0, 1.3 Hz, 1H), 2.61 (d, J = 6.5 Hz, 2H); 13C NMR (100 MHz, CD3OD) δ: 146.6, 146.4, 6.77 (deform dd, J = 8.0, 7.7 Hz, 1H), 6.64, 5.83 (2xbr.s, 2H), 2.74-2.63 125.7, 121.7, 120.8, 116.3, 75.2, 71.6, 38.9, 28.2; elemental analysis (m, 2H), 2.54-2.44 (m, 2H), 1.76-1.58 (m, 4H), 1.34 (t, J = 7.8, 1H); 13C calculated for C10H14O4S2: C, 45.78; H, 5.38; S, 24.44%; found: C, 45.81; NMR (90 MHz, CDCl3) δ: 144.4, 144.0, 126.7, 121.0, 119.3, 116.6, 36.0, H, 5.33; S, 24.46%. 32.9, 28.4, 24.3; elemental analysis calculated for C10H14O2S2: C, 52.14; H, 6.13; S, 27.84%; found: C, 52.12; H, 6.10; S, 27.79%. 6a: Pale orange S-(6-mercaptohexyl)ethanethioate 7b. Yellowish oil; IR (neat): max, oil; IR (neat): max 3460, 2931, 2545, 1578, 1339, 1201 cm−1; 1H NMR 2965, 2930, 2860, 1715, 1325, 1235, 899 cm−1; 1H NMR (360 MHz, (400 MHz, CDCl3) δ: 6.96 (dd, J = 7.7, 1.5 Hz, 2H), 6.91 (dd, J = 8.1, 1.5 CDCl3) δ: 2.84 (t, J= 7.3 Hz, 2H), 2.50 (ddd, J = 7.7, 7.4, 7.3 Hz, 2H), Hz, 2H), 6.78 (dd, J = 8.1, 7.7 Hz, 2H), 2.75-2.60 (m, 4H), 1.72-1.54 (m, 2.30 (s, 3H), 1.63-1.51 (m, 4H),1.42-1.34 (m, 4H), 1.31 (t, J= 7.7 Hz, 1H); 4H); 13C NMR (100 MHz, CDCl3) δ: 144.5, 144.2, 126.9, 121.2, 119.1, 13 C NMR (90 MHz, CDCl3) δ: 196.2, 39.2, 34.1, 30.9, 29.7, 29.3, 28.6, 116.8, 36.3, 28.8; elemental analysis calculated for C16H18O4S2: C, 24.8. 56.78; H, 5.36; S, 18.95%; found: C, 56.83; H, 5.31; S, 18.99%. S-(2-(2-(2-mercaptoethoxy)ethoxy)ethyl)ethanethioate 7c. Yellowish 3-((6-mercaptohexyl)thio)benzene-1,2-diol 5b and 3,3'-(hexane-1,6- oil; IR (neat): max, 2890, 2562, 1695, 1520, 1420, 1325, 1191, 888 cm−1; diylbis(sulfanediyl))bis(benzene-1,2-diol) 6b. Using Method A, the 1 H NMR (360 MHz, CDCl3) δ: 3.66-3.55 (m, 6H), 3.06 (t, J= 6.5 Hz, 2H), reaction mixture was purified by column chromatography with 8/2 of 2.67 (ddd, J = 8.2, 6.5, 6.4 Hz, 2H), 2.31 (s, 3H), 1.57 (t, J= 8.2 Hz, 1H); hexane/ethyl acetate, yielding 90 mg (35%) of catechol-thiol 5b, and 132 13 C NMR (90 MHz, CDCl3) δ: 195.7, 73.2, 70.5, 70.4, 70.0, 30.8, 29.1, mg (36%) of bis-catechol 6b. Using Method B, the overall yield of 5b is 24.5. 43%. 5b: Pale yellow oil; IR (neat): max 3467, 3187, 2930, 2854, 2545, 1614, 1584, 1459, 1327, 1219, 898 cm−1;1H NMR (400 MHz, CDCl3) δ: S-(6-((2,3-dihydroxyphenyl)thio)hexyl)ethanethioate 8b. After step 2 6.99 (dd, J = 7.8, 1.5 Hz, 1H), 6.92 (dd, J = 8.0, 1.5 Hz, 1H), 6.79 (dd, J = of Method B, the reaction mixture was purified by column 8.0, 7.8 Hz, 1H), 6.57, 5.35 (2xbr.s, 2H), 2.71 (dd, J =7.5, 7.3 Hz, 2H), chromatography with 7/3 hexane/ethyl acetate, yielding 133 mg (44%) of FULL PAPER 8b. Pale yellow oil; IR (neat): max 3420, 3155, 2930, 2540, 2425, 1709, trifluoroacetic acid in CH2Cl2, purged with nitrogen (5’) and a baseline 1190 cm−1; 1H NMR (360 MHz, CDCl3) δ: 6.98 (dd, J = 7.8, 1.3 Hz, 1H), recorded. After further purging (5’), 0.5 mL of a 0.1 M solution of the 6.90 (dd, J = 8.1, 1.3 Hz, 1H), 6.77 (dd, J= 8.1, 7.8 Hz, 1H), 6.58 (br. s, analyte (pyrocatechol, octadecanethiol 1a, or 3-octadecylthiocatechol 2a) 1H), 5.61 (br. s, 1H), 2.84 (t, J= 7.3 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), in CH2Cl2 were added, and the CV was recorded. Baselines and 2.32 (s, 3H), 1.60-1.50 (m, 4H), 1.45-1.30 (m, 4H); 13C NMR (90 MHz, experimental runs consisted of two consecutive oxidation/reduction CDCl3) δ: 196.5, 144.5, 144.1, 126.8, 121.0, 119.5, 116.5, 39.2, 36.7, cycles between -0.1 V and 2 V vs non-aqueous Ag/Ag+, at a 100 mV/s 35.5, 30.9, 29.7, 29.2, 28.4; HRMS (ESI) m/z calculated for C14H21O3S2 sweep rate. Prior to each experiment, the glassy carbon working [M + H]+: 301.0932; found 301.0678. electrode was polished on sandpaper (1200 grit), followed by with 1 m and 0.3 m alumina slurry on Nylon cloth. S-(2-(2-(2-((2,3-dihydroxyphenyl)thio)ethoxy)ethoxy)ethyl) ethanethioate 8c. After step 2 of Method B, the reaction mixture was Oxidative polymerization of mono-adducts (2) in ammonia/air. purified by column chromatography with 7/3 hexane/ethyl acetate, Following a previously reported procedure,[5] 0.394 g of 2a or 0.588 g of yielding 138 mg (42%) of 8c. Pale yellow oil; IR (neat): max 3433, 2927, 2b (1 mmol) were dissolved in 70 mL of isopropanol, to which 7.55 mL of 2899, 2430, 1705, 1325, 1196 cm−1; 1H NMR (360 MHz, CDCl3) δ: 7.60 NH3 aq., 25%, 100 mmol) were added. The mixture was stirred at 55°C (br. s, 1H), 6.99 (dd, J = 7.8, 1.5 Hz, 1H), 6.91 (dd, J = 8.0, 1.5 Hz, 1H), for 6 hours. After this, 60 mL of H2O were added, the organic solvent was 6.73 (dd, J = 8.0, 7.8 Hz, 1H), 5.89 (br. s, 1H), 3.68-3.64 (m, 4H), 3.61 (t, evaporated under reduced pressure, and the crude was brought to pH5 J = 6.7 Hz, 2H), 3.55 (t, J = 5.7 Hz, 2H), 3.11 (t, J = 6.7 Hz, 2H), 2.91 (t, J by dropwise addition of concentrated HCl (37%). The mixture was = 5.7 Hz, 2H), 2.33 (s, 3H); 13C NMR (90 MHz, CDCl3) δ: 196.1, 145.8, extracted with an appropriate solvent (CH2Cl2 or THF, 3 x 20 mL), dried 144.9, 127.6, 120.7, 118.8, 116.7, 70.4, 70.2, 70.1, 69.0, 36.9, 30.9, over anhydrous NaSO4, and the solvent removed under reduced 29.0; HRMS (ESI) m/z calculated for C14H21O5S2 [M + H]+: 333.0830; pressure, yielding 0.350 g (89%) of p2a (thick, black oil) or 0.505 mg found 333.0713. (86%) of p2b (black solid). Synthesis of 3,3'-[disulfanediylbis(hexane-2,1-diylsulfanediyl)] Dip-coating of macroscopic substrates. A rectangular surface (TiO2 or dibenzene-1,2-diol 9. To a solution of 55 mg of 5b (0.213 mmol) in 1.5 cotton cloth) of approx. 4 cm2 was immersed for 3 h in a 10mM solution mL of CH2Cl2, a solution of 54 mg of I2 (0.213 mmol) in 2 mL of CH2Cl2 of a mono-adduct (2a, 2b), bis-adduct (3a, 3b) or ammonia-polymerized was added dropwise. The reaction mixture was stirred at room (p2a, p2b) catechol derivative in an appropriate solvent (2a, p2a and 3a temperature for 20 min, and extracted with a 10% sodium thiosulfate in CH2Cl2, 2b, p2b and 3b in THF). The substrate was then washed solution in water. The organic phase was separated and dried over thoroughly with MeOH and dried under a N2 flow. For cotton cloth, a Na2SO4, obtaining disulfide 9 as an orange oil in quantitative yield. IR piece of about 4 cm2 was immersed for 2 min in a 1% (w/v) solution of (neat): max 3386, 2926, 2853, 1591, 1455, 1330, 1245, 1221, 1136, 1058, p2a in n-hexane or p2b in THF, rinsed, washed thoroughly with MeOH 895 cm−1; 1H NMR (360 MHz, CDCl3) δ: 7.00 (dd, J = 7.8, 1.5 Hz, 2H), and dried under a N2 flow. 6.93 (dd, J = 8.0, 1.5 Hz, 2H), 6.80 (dd, J = 8.0, 7.8 Hz, 2H), 6.58, 5.39 (2xbr.s, 4H), 2.72 (t, J =7.5 Hz, 4H), 2.67 (t, J = 7.5 Hz, 4H), 1.67 (m, Coating of mesoporous silica nanoparticles (MSNs).To a solution of 8H), 1.40 (broad m, 8H); 13C NMR (90 MHz, CDCl3) δ: 144.2, 143.8, 51.4 mg of 9 (0.1 mmol) in 13 mL of isopropanol, 5 mg of MSNs (Ø  250 126.6, 120.8, 119.1, 116.3, 38.8, 36.6, 29.5, 28.9, 28.1, 27.9 HRMS (ESI) nm) and 0.75 mL of 25% wt aqueous ammonia (10 mmol) were added. m/z calculated for C18H22NaO4S2 [M + Na]+: 389.0857; found 389.1238. The suspension was stirred at 200 rpm and 45°C for 16 h, centrifuged (7500 rpm, 5 min) and washed successively with 1x3 mL of water and Synthesis of 6-((2,3-dihydroxyphenyl)thio)hexyl(3,6-dihydroxy-3'- 2x3 mL of EtOH. oxo-3'H,10H-spiro[anthracene-9,1'-isobenzofuran]-5'-yl) carbamodithioate 10. To a solution of 55 mg of 5b (0.21 mmol) in 4 mL Coating of magnetite nanoparticles. 300 μL of a suspension of oleic- of acetone, 83 mg of fluorescein isothiocyanate (0.21 mmol) were added, acid stabilized iron oxide (FexOy) nanoparticles in n-hexane (ca. 20 and the reaction mixture refluxed under magnetic stirring for 24 h. The mg/mL) was added to a solution of 15 mg of 2c (0.017 mmol) in 1 mL solvent was then removed under reduced pressure, and the residue CH2Cl2, and stirred for 15 hours. After this, the sample was centrifuged, purified by column chromatography with 6/4 hexane/ethyl acetate, washing once with CH2Cl2 and 4 times with n-hexane. Iron oxide NPs yielding 83 mg (60%) of 10 as a dark orange solid (λex = 450 nm, λem = were then re-suspended in a water/n-hexane mixture and shaken, where 520 nm). IR (neat): max 3552, 3490, 3325, 3182, 2920, 2899, 2535, 1725, they were shown to extract to the aqueous layer. 1695, 1565, 1455, 1390, 1173 cm−1; 1H NMR (360 MHz, (CD3)2CO) δ: 10.9 (br.s, 1H), 8.90 (br.s, 1H), 8.58 (s, 1H), 8.11 (dd, dd, J = 8.3, 2.0 Hz, Synthesis of theranostic CPPs with 10 as fluorescent ligand. A 1H), 7.30 (dd, J = 8.3, 0.5 Hz, 1H), 6.86 (dd, J = 7.8, 1.6 Hz, 1H), 6.78 mixture of 48 mg (0.195 mmol) of L-DOPA methyl ester hydrochloride, 3 (dd, J = 8.0, 1.6 Hz, 1H), 6.76 (s, 2H), 6.75-6.70 (m, 2H), 6.71 (s, 2H), mg (0.0046 mmol) of 10 and 24 mg (0.1 mmol) of 1,4-bis(imidazol-1- 6.66 (dd, J= 8.0, 7.8 Hz, 1H), 6.64 (d, J= 8.7 Hz, 1H), 3.32 (dd, J = 7.5, ylmethyl)benzene (BIX) were dissolved in 12 mL of EtOH. Under 7.2 Hz, 2H), 2.84 (t, J = 7.2 Hz, 2H), 1.72 (p, J = 7.3 Hz, 2H), 1.60 (p, J = magnetic stirring (1000 rpm), an aqueous solution of 25 mg (0.10 mmol) 7.4 Hz, 2H), 1.53-1.39 (m, 4H), Catechol-OH nd; 13C NMR (90 MHz, of Co(AcO)2·4H2O in 1.6 mL of water was added to the alcoholic solution. (CD3)2CO) δ: 199.1, 160.3, 153.3, 150.7, 145.7, 145.6, 142.2, 131.2, A brown suspension was rapidly formed, which was stirred at room 130.1, 128.3, 125.2, 124.1, 122.2, 120.6, 119.1, 115.4, 113.3, 111.4, temperature for 2 h. After incubation, the suspended solid was recovered 103.3, 35.7, 34.3, 30.6, 29.9, 29.5, 29.0, 28.8; HRMS (ESI) m/z by centrifugation at 8000 rpm for 10 min, the resultant pellet was re- calculated for C33H30NO7S3 [M + H]+: 648.1184; found 648.1162. suspended in EtOH (12 mL) and washed several times, until no free L- DOPA methyl ester or 10 were detected by fluorescence in the Cyclic voltammetry. Prior to the experimental runs, a 50 mM stock supernatant. The final pellet containing fluorescent coordination polymer solution of tetrabutylammonium hexafluorophosphate (TBAPF6) in nanoparticles was re-suspended in 1.5 mL EtOH and stored in solution at CH2Cl2 previously dried over molecular sieves (4 Å) was used to prepare 4°C. For fluorescence measurements, samples were re-suspended in the test medium, as well as to set up the non-aqueous Ag/Ag+ (10 mM water and fluorescence emission registered between 400 and 700 nm AgNO3) reference electrode. For each experiment, 9 mL of the stock (ex = 450 nm). electrolyte solution were mixed with 0.5 mL of a 0.3 M solution of FULL PAPER Cell culture and cellular uptake of fluorescent CPNPs. Human BE(2)- [4] H. Lee, S. M. Dellatore, W. M. Miller, P. B. Messersmith, Science 2007, M17 cells were maintained in Opti-MEM medium further supplemented 318, 426-430. with 10 % (v/v) of heat-inactivated fetal bovine serum (FBS). Cells were [5] a) J. Sedó, J. Saiz-Poseu, F. Busqué, D. Ruiz-Molina, Adv. Mater. 2013, grown under a highly humidified atmosphere of 95 % air with 5 % CO2 at 25, 653-701; b) B. García, J. Saiz-Poseu, R. Gras-Charles, J. 37 °C. Cellular uptake of the nanoparticles was monitored by using in Hernando, R. Alibés, F. Novio, J. Sedó, F. Busqué, D. Ruiz-Molina, laser scanning confocal microscopy (LSCM). For in vitro imaging, BE(2)- ACS Appl. Mater. Interfaces 2014, 6, 17616-17625; M17 cells were seeded in a 35 mm glass-bottom culture dishes at a [6] a) J. Saiz-Poseu, J. Sedó, B. García, C. Benaiges, T. Parella, R. Alibés, density of 1.0x105 cells per dish. After 24 h incubation the media was J. Hernando, F. Busqué, D. Ruiz-Molina, Adv. Mater. 2013, 25, 2066- removed and cells were treated with control medium or with 50 µg/mL of 2070; b) J. Kumanotani, Prog. Org. Coat. 1999, 26, 163; c) M. A. fluorescent CPPs for 6 h at 37 °C. Simultaneously to the nanoparticles, ElSohly, P. D. Adawadkar, C. Ma, C. E. Turner, J. Nat. Prod. 1982, 45, Lyso Tracker® Red at a final concentration of 75 nM was added to the 532-538; d) N. N Adarsh, F. Novio, D. Ruiz-Molina, Dalton Trans., 2016, cells. Immediately before imaging, cells were washed three times with 1 45, 11233-11255. mL of fresh medium, and then nuclei and membranes were stained with [7] a) I. Y. Chukicheva, I. V. Timusheva, L. V. Spirikhin, A. V. Kuchin, Chem. 5 µg/mL Hoechst (Invitrogen) and 1X Cell Mask for 10 min at 37 °C. Cells Nat. Compd. 2007, 43, 245-249; b) E. Findik, M. Ceylan, M. Elmastas, were imaged in vitro at 37 °C. Eur. J. Med. Chem. 2011, 46, 4618-4624; c) J. Duan, W. Wu, Z. Wei, D. Zhu, J. Tu, A. Zhang, Green Chem. 2018, 20, 912-920. [8] Y. Kuninobu, T. Matsuki, K. Takai, J. Am. Chem. Soc. 2009, 131, 9914- 9915. Conflict of interest [9] X. Liu, Y. Ou, S. Chen, X. Lu, H. Cheng, X. Jia, D. Wang, G.-C. Zhou, Eur. J. Med. Chem. 2010, 45, 2147-2153. The authors declare no conflict of interest. [10] H. Naeimi, L. Moradi, J. Mol. Cat. A: Chem. 2006, 256, 242-246. [11] J. Yu, W. Wei, E. Danner, R. K. Ashley, J. N. Israelachvili, J. H. Waite, Nat. Chem. Biol. 2011, 7, 588-590. [12] a) K. Cao, D. E. Stack, R. Ramanathan, M. L. Gross, E. G. Rogan, E. L. Acknowledgements Cavalieri, Chem. Res. Toxicol. 1998, 11, 909-916; b) R. Micillo, L. Panzella, K. Koike, G. Monfrecola, A. Napolitano, M. d’ Ischia, C.C. and M.A.M.-V. are grateful to the Spanish Ministry of International Journal of Molecular Sciences 2016, 17, 746-758. Science for their pre-doctoral grants (FPU-2015-03245 and FPI- [13] a) K. S. Feldman, A. Sambandam, K. E. Bowers, H. M. Appel, J. Org. SEV-2013-0295-16-1). F.N. is grateful to the Universidad Chem. 1999, 64, 5794-5803; b) J. S. Mitchell, Y. Wu, C. J. Cook, L. Main, Bioconjugate Chem. 2007, 18, 268-274; c) L. A. Miller, M. A. Nacional del Sur for a postdoctoral grant. This project had Marsini, T. R. R. Pettus, Org. Lett. 2009, 11, 1955-1958; d) T. Masuda, financial support from the Spanish Ministry of Science and EU M. Inai, Y. Miura, A. Masuda, S. Yamauchi, J. Agric. Food Chem. 2013, FEDER funds (CTQ2016-75363-R and MAT2015-70615-R). We 61, 1097-1104; e) A. Kotronoulas, N. Pizarro, A. Serra, P. Robledo, J. thank Prof. Antonio Frontera (Universitat de les Illes Balears) for Joglar, L. Rubio, A. Hernaéz, C. Tormos, M. J. Motilva, M. Fitó, M.-I. the use of computational facilities and assistance in calculations. Covas, R. Solà, M. Farré, G. Saez, R. de la Torre, Pharmacol. Res. 2013, 77, 47-56; f) Y. S. Cheah, S. Santhanakrishnan, M. B. Sullivan, K. G. Neoh, C. L. L. Chai, Tetrahedron 2016, 72, 6543-6550. Keywords: catechol chemistry • bioinspired materials • thiol [14] a) B. V. Varun, K, R. Prabhu, J. Org. Chem. 2014, 79, 9655-9668; b) H. conjugate addition • functional coatings • surface wetting • T. Abdel-Mohsen, J. Conrad U. Beifuss, Green Chem. 2014, 16, 90-95; coordination polymers • theranostics c) P. Bandyopadhyay, B. Bhattacharya, K. Majhi, P. Majee, U. Sarkar, M. Md. Seikh, Chem. Phys. Lett. 2017, 686, 88-96. [1] a) J. H. Waite, M. L. Tanzer, Science 1981, 212, 1038-1040; b) J. H. [15] E. Adler, R. Magnusson, Acta Chem. Scand. 1959, 13, 505-519. Waite, X.X. Qin, Biochemistry 2001, 40, 2887-2893.; c) L. A. Burzio, J. [16] J. Yang, M. A. Cohen-Stuart, M. Kamperman, Chem. Soc. Rev. 2014, H. Waite, Biochemistry 2000, 39, 11147-11153; d) M. J. Sever, J. T. 43, 8271-8298. Weisser, J. Monahan, S. Srinivasan, J. J. Wilker, Angew. Chem. Int. Ed. [17] a) F. Nador, F. Novio, D. Ruiz-Molina, Chem. Commun. 2014, 50, 2004, 43, 448-;450 e) M. Yu, J. Hwang, T. J. Deming, J. Am. Chem. 14570-14572. b) M. A. Moreno-Villaécija, J. Sedó-Vegara, E. Guisasola, Soc. 1999, 121, 5825-5826; f) V. V. Papov, T. V. Diamond, K. Biemann, A. Baeza, M. Vallet-Regí, F. Nador, D. Ruiz-Molina ACS Appl. Mater. J. H. Waite, J. Biol. Chem. 1995, 270, 20183-20192.;g) J. Saiz-Poseu, Interfaces 2018, 10, 7661-7669. J. Mancebo-Aracil, F. Nador, F. Busqué, D. Ruiz-Molina, Angew. Chem. [18] a) F. Meng., X. Li., S. Torker., Y. Shi, X. Shen, A. H. Hoveyda, Nature, Int. Ed. 2019, 58, 696-714. 2016, 537, 387-393; b) T. A. Mohamed, A. M. Mustafa, W. M. Zoghaib, [2] a) M. Yu , T. J. Deming, Macromolecules 1998, 31, 4739-4745; b) B. P. M. S. Afifi, R. S. Farag, Y. Badr, J. Mol. Struct. THEOCHEM 2008, 868, Lee, C.-Y. Chao, F. N. Nunalee, E. Motan, K. R. Shull, P. B. 27-36. Messersmith, Macromolecules 2006, 39, 1740-1748; c) S. A. Burke, M. [19] a) J. Kumanotani, Prog. Org. Coat. 1999, 26, 163; b) M. A. ElSohly, P. Ritter-Jones, B. P. Lee, P. B. Messersmith, Biomed. Mater. 2007, 2, D. Adawadkar, C. Ma, C. E. Turner, J. Nat. Prod. 1982, 45, 532-538. 203-210; d) G. Westwood, T. N. Horton, J. J. Wilker, Macromolecules, [20] N. N Adarsh, F. Novio, D. Ruiz-Molina, Dalton Trans., 2016, 45, 11233- 2007, 40, 3960-3964. 11255. [3] a) S. Saxer, C. Portmann, S. Tosatti, K. Gademann, S. Zürcher, M. [21] P. K. Dhal, F. H. Arnold, Macromolecules 1992, 25, 7051-7059. Textor, Macromolecules 2010, 43, 1050-1060; b) H. Han, J. Wu, C. W. [22] J. Park, K. An, Y. Hwang, J.-G. Park, H.-J. Noh, J.-Y. Kim, J.-H. Park, Avery, M. Mizutani, X. Jiang, M. Kamaigaito, Z. Chen, C. Xi, R. Lu, Y. N.-M. Hwang, T. Hyeon, Nat. Mater. 2004, 3, 891-895. Kamiya, T. Miyakoshi, Talanta 2006, 70, 370-376; c) B. Malisova, S. [23] C. Adamo, V. Barone, J. Chem. Phys. 1999, 110, 6158-6170. Tosatti, M. Textor, K. Gademann, S. Zürcher, Langmuir 2010, 26, 4018- [24] A. Schäfer, C. Huber, R. Ahlrichs, J. Chem. Phys. 1994, 100, 5829-5835. 4026; d) J. L. Dalsin, L. Lin, S. Tosatti, J. Vörös, M. Textor, P. B. [25] a) S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132, Messersmith, Langmuir 2005, 21, 640-646; e) J. L. Dalsin, B.-H. Hu, B. 154104-154119; b) R. Ahlrichs, M. Bär, M. Hacer, H. Horn, C. Kömel, P. Lee, P. B. Messersmith, J. Am. Chem. Soc. 2003, 125, 4253-4258. Chem. Phys. Lett. 1989, 162, 165-169. [26] J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005, 105, 2999-3094. FULL PAPER [27] Gaussian 16, Revision A.03, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2016. [28] a) J. Contreras-García, E. R. Johnson, S. Keinan, R. Chaudret, J. -P. Piquemal, D. N. Beratan, W. Yang, J. Chem. Theory Comput. 2011, 7, 625-632; b) R. F. W. Bader, Chem. Rev. 1991, 91, 893-928; c) AIMAll Version 13.05.06, Todd A. Keith, TK Gristmill Software, Overland Park KS, USA, 2013. FULL PAPER Entry for the Table of Contents (Please choose one layout) Layout 1: FULL PAPER Text for Table of Contents Juan Mancebo-Aracil,* Carolina Casagualda, Miguel Ángel Moreno- Villaécija, Fabiana Nador, Javier García- Pardo, Antonio Franconetti-García, Félix Busqué, Ramon Alibés, María José Esplandiu, Daniel Ruiz-Molina, Josep Sedó-Vegara* Page No. – Page No. Bioinspired Functional Catechol Derivatives Through Simple Thiol Conjugate Addition