Chemistry

Easy Tyrosine Derivatives Act as Low Molecular Weight Organogelators

Spontaneous Gelation of L-Tyr(tBu)-OH (2)

L-Tyr(tBu)-OH is a reasonable commercially obtainable compound and can also be synthetically simple to supply quantitatively in a single step from Fmoc-L-Tyr(tBu)-OH29. Gelation happens spontaneously throughout the next response (Fig. 1).

Determine 1Figure 1

Synthesis of L-Tyr(tBu)-OH.

The cleavage of the fluorenylmethyloxycarbonyl (Fmoc) group with piperidine in THF resulted in gelation inside 15 minutes in the course of the response. After the elimination of the by-product, gelation was efficiently achieved underneath the identical situations utilizing pure L-Tyr(tBu)-OH which signifies that the by-product doesn’t play a job within the gelation course of. This response was initially carried out aiming to synthesize unprotected tyrosine for use in one other examine and finally led us to the serendipitous discovery of this new organogelator, which triggered additional investigations as reported hereafter.

Identical gelation properties have been noticed for the opposite enantiomer, D-Tyr(tBu)-OH, as anticipated. Nevertheless, no gel formation was noticed within the case of racemic Tyr(tBu)-OH at minimal gelation focus. As well as, we noticed that the tert-butyl moiety performs a major position within the gelation course of, since gel formation doesn’t happen for both L-Tyr-OH, L-Phe-OH and L-Tyr(Me)-OH.

Additive and solvent screening for gelation

To be able to examine the gelation properties of L-Tyr(tBu)-OH, totally different combos of components and solvents have been thought of utilizing the vial inversion methodology (Tables 1 and a couple of). Desk 1 summarizes the consequences of the totally different components (bases and alcohols) on gelation in THF.

Desk 1 Gelation outcomes of L-Tyr(tBu)-OH with totally different components in THF.Desk 2 Gelation outcomes of L-Tyr(tBu)-OH in several solvents with and with out non-gelling agent. The values are given in wt/v%.

Gels have been ready in 1.zero mL of THF. After dissolution of L-Tyr(tBu)-OH in solvent with the assistance of ultrasonic bathtub at 40 °C, 10.zero μL of additive was added. The options have been positioned once more into ultrasonic bathtub for four–10 minutes. The formation of the gels was decided utilizing inversion take a look at.

L-Tyr(tBu)-OH types a gel in THF with a minimal focus of 1.1 wt/v% with out the usage of any additive. Surprisingly, the addition of piperidine lowers the minimal gel focus to zero.45 wt/v%. Gelation additionally happens within the presence of different bases, comparable to diisopropylamine, diethylamine and imidazole, albeit with weaker gel appearances. Nevertheless, when triethylamine and DBU is used as additive, a suspension and a transparent answer is fashioned, respectively. This consequence means that the additive must also have donor-acceptor hydrogen bond skill to set off gel formation. To additional take a look at this speculation, short-alkyl-chain-containing alcohols have been additionally thought of however have been discovered to play no beneficial position within the gelation course of as an additive. Alternatively, 2-ethylhexanol does present vital impact on gelation, which signifies that van der Waals interactions between additive and organogelator additionally lower the minimal gelation focus. Beside these natural bases and alcohols, the addition of 1 eq. of NaOH resulted in a minimal gelation focus as little as zero.25 wt/v% in THF. These outcomes present that components will not be essentially concerned within the hydrogen bond community, however that the amine-type components are additionally appearing as a base, which deprotonates the carboxylic acid, permitting the ensuing carboxylate group to raised take part within the hydrogen bond community. That is additionally in line with the upper minimal gelation concentrations noticed when short-alkyl-chain-containing alcohols have been used as components, since alcohols are weakly acidic.

The gelation of L-Tyr(tBu)-OH was additional examined in all kinds of solvents with or with out the addition of the non-gelling agent, piperidine or NaOH. As proven in Desk 2, L-Tyr(tBu)-OH types a gel with all kinds of natural solvents at remarkably low concentrations.

Among the many examined situations, DMF seems as the most effective solvent for gelation, with a capability to gel at zero.1 wt/v% with none additive. Additional, 2-ethylhexanol, when used as a solvent, exhibits promising gelation outcomes with a focus as little as zero.2 wt/v%. The addition of a non-gelling agent to the latter gel merely modifications the looks of the gel to clear and doesn’t have a major influence on the minimal gelation focus. Equally, toluene, hexane, and 1,2-dichloroethane additionally look like good solvents for gelation solely with the addition of piperidine. Presence of piperidine decreases the gelation focus for the solvents tert-butylmethylether and 1,2-dimethoxyethane, of which they fashioned answer on the outlined concentrations with out components. Surprisingly, cellulose thinner, isopropylalcohol, and n-butylalcohol, when used as solvents, end in a transparent gel with out piperidine, whereas the addition of piperidine types options. The gelation of sunflower oil signifies a promising potential software of L-Tyr(tBu)-OH within the discipline of drug supply30,31,32. Equally, the gelation of diesel by L-Tyr(tBu)-OH was noticed, indicating a attainable operate in oil-spill recovery3,10.

Gelation and Fluoride Ion Response of L-Tyr(TBDMS)-OH

We synthesized L-Tyr(TBDMS)-OH (Fig. 2a) and investigated its gelation properties underneath numerous situations. The gelation of this spinoff was achieved in each THF and 2-ethylhexanol, with a minimal focus of 1 wt/v% in each solvents. L-Tyr(TBDMS)-OH is delicate to the presence of fluoride, for the reason that latter can set off the cleavage of the Si-O bond to type L-Tyr-OH, as depicted in Fig. 2b. The addition of sodium fluoride to L-Tyr(TBDMS)-OH gels in 2-ethylhexanol in concentrations of zero.2, zero.three and zero.5 ppm resulted in an entire gel to answer transition inside 44 h, 18 h, and 1 h, respectively (Fig. 2c). Fluoride ion cleave the TBDMS moiety to yield L-Tyr-OH, which, as beforehand mentioned, doesn’t present gelation properties in 2-ethylhexanol, explaining the gel to answer transition noticed after a sure time frame. We due to this fact counsel L-Tyr(TBDMS)-OH as a probably promising gelator that can be utilized for the detection of fluoride ions.

Determine 2Figure 2

(a) Synthesis of L-Tyr(TBDMS)-OH (b) Si-O bond cleavage of L-Tyr(TBDMS)-OH within the presence of fluoride ion. (c) Picture of full gel to answer transition of two wt/v% of L-Tyr(TBDMS)-OH in 2-ethylhexanol as solvent and piperidine as additive after 1 hour upon addition of zero.5 ppm NaF(aq.)

Characterization of Microstructures and Gel Behaviours

The characterization of the microstructure of the L-Tyr(tBu)-OH gel in addition to the molecular packing at an atomic scale was carried out utilizing transmission electron microscope (TEM) imaging (Fig. 3a), X-ray powder diffraction (XRD) measurements (Fig. 3b), and molecular dynamics (MD) simulations.

Determine threeFigure 3

(a) TEM pictures of L-Tyr(tBu)-OH in THF/piperidine diluted with miliQ water. (Scale bar: 200 nm and 500 nm). (b) XRD sample of xerogels with and with out piperidine.

In Fig. 3a, the TEM pictures of the L-Tyr(tBu)-OH in THF with the addition of piperidine present the formation of nanofibres with an approximate width of 40 nm and a size of a number of micrometres. The XRD patterns reported in Fig. 3b for the samples ready with and with out piperidine additive point out that piperidine doesn’t take part within the molecular packing, for the reason that two patterns are practically equivalent.

MD simulation of L-Tyr(tBu)-OH in THF resulted within the spontaneous formation of aggregates stabilized by robust hydrogen bond interactions between the carboxylate and ammonium teams of the gelator (Fig. S7a). The same simulation together with piperidine molecules additionally resulted in a spontaneous self-assembly, although with a considerably totally different interplay motif (Fig. S7b).

As such a unique molecular packing would end in a unique XRD sample, we due to this fact positively rule out the structural position of piperidine within the formation of the gel. The corresponding outcomes are additional mentioned within the Supporting Data. The following microsecond-long MD simulation of pure L-Tyr(tBu)-OH highlights the formation of lengthy networks of interacting molecules, which type a sequence of parallel packed fibre-like constructions (Fig. four), in settlement with the TEM imaging.

Determine fourFigure 4

Illustration of the fibre-like construction as obtained after one microsecond MD simulation of pure L-Tyr(tBu)-OH. (a,b) Respectively present a facet and prime view of the simulation field with its periodic pictures. The dotted traces delimit the primary unit cell wherein spine and facet chains carbon atoms of every molecule are depicted in cyan. Solely the spine atoms, forming the core of every fibre are proven for the reproduction to spotlight the linear construction of the totally different assemblies. A consultant construction of two interacting fibres is proven in (c), with two representations to indicate the entire molecules on the left-hand facet and to spotlight the interactions within the core of the fibres solely on the right-hand facet. Hydrogen bonds are represented with dashed blue traces and present the community by which the person molecules work together to type fibres and punctually bridge them collectively.

As highlighted in Fig. 4c and additional detailed in Fig. S7, every fibre consists of a hydrophilic core with a robust and compact community of hydrogen bonds, whereas the hydrophobic facet chains level outward and guarantee interactions between fibres. We additionally famous the sporadic incidence of hydrogen bonds branching between the fibres, that are more likely to take part within the general stability of the molecular meeting. The evaluation of radial distribution features (RDF; Fig. S8) for particular pairs of atoms alongside the dynamics revealed a sequence of well-defined peaks centred at distances in line with the diffractions seen within the XRD sample. Our simulations confirmed no proof of secure π−π stacking interplay between fragrant rings of L-Tyr(tBu)-OH, which is most certainly as a result of massive steric hindrance by tBu teams. As an alternative, the sharp and intense peak at 2θ = 26.65° (dhkl = three.34 Å) within the XRD sample may be attributed to the tight interplay noticed between carboxylate and ammonium teams alongside the simulation, with a carbon-nitrogen RDF strongly peaking at a distance of three.33 Å. Extra discussions, simulations particulars, and parameter recordsdata are additionally obtainable within the Supporting Data.

The gelation course of is triggered by driving forces just like these at play within the formation of reverse micelles. The hydrophobic character of the solvent enhances the tendency of the polar a part of L-Tyr(tBu)-OH molecules to work together with one another, in an remoted core with hydrophobic tBu teams pointing in the direction of the solvent. Not like micelles, nonetheless, the small dimension of the hydrophilic amino acid spine along with the extremely directional and dipolar character of the interacting chemical teams favours the formation of a linear community slightly than spherically formed vesicles. As predicted by MD simulations (Figs four and S8) this linear community can department via the interconnection of fibres through hydrogen bonds and van der Waals interplay. This final statement leads us to postulate that the gelation outcomes from the formation of a three-dimensional grid of interconnected fibre-like constructions in answer.

In abstract, L-Tyr(tBu)-OH and L-Tyr(TBDMS)-OH are forming gels resulting from a dense community of hydrogen bonds between ammonium and carboxylate teams. Quite a lot of amino acid-derived organogelators have been reported within the literature, presenting substitution both on the amine or on the carboxyl group. To the most effective our data, nonetheless, there was so far no report of a pure amino acid-derived organogelator bearing free -NH2 and –COOH teams, which we confirmed right here to be the primary issue affecting the three-dimensional construction of the gel. Additionally, tert-butyl moiety seems to play a vital position within the gelation course of by stopping the π−π interactions resulting from its steric hindrance. That is additional confirmed by the incapability of L-Tyr(OMe)-OH to type a gel. The methyl group appears to be too small to stop the π−π interactions, resulting in precipitation as a substitute of gelation in THF.

Rheological measurements have been carried out to research the gel behaviours of each compounds, L-Tyr(tBu)-OH and L-Tyr(TBDMS)-OH (Fig. 5). A big distinction between dynamic storage modulus G″ and loss modulus G′ in any respect frequencies signifies that the organogels in query present elastic character as a delicate matter dominantly. To show the beneficial impact of non-gelling additive on the gel, piperidine added gel was additionally investigated (Fig. 5a). Though we confirmed that the piperidine components didn’t take part within the molecular construction of the gel, the rheological outcomes clearly confirmed that such non-gelling components enhanced the gel properties. The higher distinction between G″ and G′ for the piperidine containing organogel in comparison with additive free organogel leads us to conclude that the presence of non-gelling additive enhanced the gel properties of those delicate materials.

Determine 5Figure 5

Viscoelastic behaviour of (a) 1 wt/v% L-Tyr(tBu)-OH in 2-ethylhexanol and 2-ethylhexanol/piperidine; (b) 1 wt/v% L-Tyr(TBDMS)-OH in 2-ethylhexanol/piperidine.


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