DOI: 10.1002/chem.201501386
Full Paper
& Click Chemistry
Dendrimers with Oligospiroketal (OSK) Building Blocks: Synthesis and Properties Pablo Wessig,*[a] Dennis Budach,[a] and Andreas F. Thìnemann[b] Dedicated to Professor Bernd Giese on the occasion of his 75th birthday
Abstract: The development of novel dendrimers containing oligospiroketal (OSK) rods as building blocks is described. The linkage between the core unit (CU), branching units (BU), and OSK rods relies on the CuAAC reaction between terminal alkynes and azides. Two different strategies of dendrimer synthesis were investigated and it was found that the
Introduction Dendrimers are tree-like large molecules, which are characterized by repetitively occurring branches.[1, 2] In contrast to polymers they are monodisperse and, in most cases, highly symmetric. In recent decades, countless publications about dendrimers have been released and meanwhile they have found widespread application in material science,[2a, d] catalysis,[2a, b] and pharmaceutical chemistry (especially in drug delivery).[2c, e] The physical and biological properties of dendrimers depend on the conformational rigidity of the individual building blocks. This applies especially to the apparent size of dendrimer molecules, derivable from their hydrodynamic radius.[3] Dendrimers consisting of rather flexible elements tend towards entanglement and back-folding and thus minimize their entropy. This can be countered by utilizing molecular rods[6] as additional building blocks. Admittedly, this approach has seldom been used and, herein, we wish to report on investigations on the synthesis and outstanding properties of dendrimers bearing rigid rods as structural elements.[7] Several years ago we developed a new class of molecular rods whose key elements are ketal structures. We therefore called these rods oligospiroketal (OSK) rods.[6–13] The backbone of these rods consists of spirocyclically joined 1,3-dioxane and [a] Prof. Dr. P. Wessig, Dr. D. Budach Institut fìr Chemie, Universitt Potsdam Karl-Liebknecht-Str. 24–25, 14476 Potsdam (Germany) Fax: (+ 49) 3319775065 E-mail: [email protected] Homepage: http://ag-wessig.chem.uni-potsdam.de [b] Prof. Dr. A. F. Thìnemann Bundesanstalt fìr Materialforschung und -prìfung Unter den Eichen 87, 12205 Berlin (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201501386. Chem. Eur. J. 2015, 21, 10466 – 10471
convergent approach is clearly superior to the divergent one. SAXS measurements and MD simulations indicate that the obtained dendrimer features a globular structure with very low density. Obviously, the OSK rods stabilize a rather loose mass-fractal structure.
cyclohexane rings. Terminal functionalities are introduced, for example, by piperidine-4-one derivatives. Meanwhile, we disclosed several applications of OSK rods in biological systems,[8, 9, 12] as rigid spacers[11] and as building blocks in porous materials.[13] In general, dendrimers consist of a core unit with three or more connecting points, branching units, and terminal functionalities. A highly efficient coupling reaction is the decisive precondition for the successful synthesis of a dendrimer. Several coupling reactions have been applied in this context, in which the copper-catalyzed [3+ +2] cycloaddition between azides and terminal alkynes (copper-catalyzed alkyne-azide cycloaddition, CuAAC, click-reaction)[14] has been frequently employed.[15] Therefore, we also used this powerful method in this work.
Results and Discussion Building blocks As mentioned above, all dendrimers exhibit a multivalent core unit (CU). Because the CuAAC between terminal alkynes and azides was supposed to be the build-up reaction, we choose the tetrapropargyl ether of pentaerythritol (1) as the Figure 1. Core unit (CU) 1. core unit (Figure 1).[16] The required branching units (BU) should possess the following structural features: an azide and at least two terminal alkynes, protected with trimethylsilyl groups. The synthesis of the first BU commences with alcohol 2, which is known in the literature[17] and is readily available from reactions with methyl gallate. The alkyne moieties were protected with TMS groups. The resulting alcohol 3 was converted to the azide 5 in two steps
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Scheme 3. Synthesis of OSK rod 16; i) TMSCl/NaH, toluene, ii) lauroyl chloride/DIPEA, DCM, iii) (COCl)2/DMSO, DCM, iv) TMSOTf, DCM, v) NaN3, DMF; R = C11H23. Scheme 1. Synthesis of branching unit 5; i) BuLi/TMSCl, THF, ii) CBr4/PPh3, DMF, iii) NaN3, DMF.
to Noyori’s method[19] using the bis-trimethylsilyl-ether 12, which was prepared from the known diol 11.[9] Finally, the chloroacetyl group was converted into an azidoacetyl group with quantitative yield giving the rod 16 (Scheme 3). Divergent approach There are fundamentally two ways to construct a dendrimer. The divergent approach starts with CU and builds up the dendrimer by repetitive introduction of BUs or alternating introduction of BUs and extension building blocks. We initially pursued this approach. Due to the pivotal relevance of the CuAAC in our dendrimer synthesis we first undertook an optimization of the click conditions by means of the CU 1 and the BU 5 (Scheme 4).
Scheme 2. Synthesis of OSK rod 10; i) 4-nitrophenyl 3-(trimethylsilyl)-2-propynyl carbonate,[18] DCM, ii) (COCl)2/DMSO, DCM, iii) 1. NaH,TMSCl, 2. TMSOTf, DCM.
and with excellent yields (Scheme 1, a second BU was used in the convergent approach, see below). There are two ways to incorporate OSK rods into the dendrimers: 1) as an extending unit between CUs and BUs or between two BUs, or 2) as terminal units at the periphery of the dendrimer. For both approaches we developed appropriately functionalized OSK rods. It should be noted that we used trispiranes as model rods to reduce the synthetic effort. The synthetic route to the first type of rods is outlined in Scheme 2. 4Hydroxypiperidine 6 is first converted to the TMS-protected propargyl carbamate 7, which was then oxidized to the ketone 8. Reaction of 8 with the previously developed azido-diol 9[9] using the method of double activation[8] afforded the OSK rod 10 (Scheme 2). Similarly, we prepared the terminal OSK rods. For this purpose 4-hydroxypiperidine 6 was first lauroylated for solubility enhancement of the dendrimers and then oxidized to ketone 14. The construction of the trispirane 15 took place according Chem. Eur. J. 2015, 21, 10466 – 10471
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Scheme 4. CuAAC reaction between 1 and 5 (for conditions, see Table 1).
For this purpose we investigated three different catalyst systems, which are summarized in Table 1. The resulting product mixtures were analyzed with MALDI-TOF mass spectrometry
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Full Paper Table 1. Click conditions A–C. Entry
Catalyst
Conditions
Ref.
A B
CuBr/TREN-Bn6[a] Cu/C
[20] [21]
C
CuSO4/ascorbate
4 equiv cat., toluene, reflux, 24 h 4 equiv cat., 1 equiv Et3N, DCM, RT, 24 h 8 equiv cat., H2O/tBuOH/DCM, 24 h
[a] TREN-Bn6 = hexabenzyl-tris(aminoethyl)amine.
[22]
After the catalyst optimization we applied these settings to the click reaction of CU 1 and rod 10. Once again we obtained the desired fourfold substituted product 18 beside nearly the same amounts of threefold substituted product (Scheme 5). Moreover, we detected signals in the MALDI-TOF mass spectrum, which could be explained by the cleavage of one TMS group in 18, followed by a repeated click reaction with 10 (see the Supporting Information). Although the mixture containing 18 could not be separated, we continued with the dendrimer synthesis. After cleavage of TMS groups giving 19 the click reaction with BU 5 using Cu/C catalyst was performed. The target compound 20 could indeed be detected in the mass spectra but only as minor component (Scheme 6). Subsequent attempts to convert 20 to a dendrimer were not successful. Clearly, it is not possible to prepare dendrimers by this approach due to a) incomplete click reactions and b) partial cleavage of TMS protecting groups during the click reaction followed by an undesired repeated click reaction. Convergent approach
Figure 2. MALDI-TOF mass spectra of 17 obtained with catalysts A–C (4x = blue symbols, 3x = red symbols, 2x = green symbols).
After the rather sobering experience with the divergent approach we now turned to the convergent approach. The deciding feature of this approach is that at first a “branch” is prepared, which is then connected with the core unit in the final step of the dendrimer synthesis. The branch synthesis commences with two building blocks: the piperidin-4-one 21[9] and the diol 22.[24] After acetalization between these compounds to spirane 23, a click reaction with rod 16 was performed. The resulting chloroacetyl derivative 24 was converted into the azide 25 in the final step (Scheme 7). To our delight, the branch building block 25 could be successfully coupled with the CU 1 to give the dendrimer 26 with 38 % yield. It is noteworthy that, in contrast to the product mixtures obtained with the divergent approach, 26 could be easily purified by simple flash chromatography (Scheme 8).
and a comparison of the corresponding spectra is depicted in Figure 2. In all cases we detected the desired product 17 with fourfold cycloaddition (blue symbols) of 5 to 1 (m/z = 2332, ^). The product peak is accompanied either by a peak of the Na + adduct (m/z = 2355, *, cond. A), the K + adduct (m/z = 2371, &, cond. B), the adduct with [2Cu] + (m/z = 2458, !, cond. B) or the adduct with Cu + (m/z = 2397, N, cond. C). Furthermore, with catalysts A and C, we also observed the analogous signals of threefold (red symbols) and twofold substituted products. In the MALDI-TOF mass spectrum of the mixture obtained with catalyst A we also observed peaks at 1536, 2050 and 2563 Da, which could be assigned to adducts with [3Cu + K] + (fl). To sum up, the highest selectivity was achieved with the Cu/C catalyst B. It should be noted that we obtained similar results very recently in connection with the synthesis of molecular rods.[23] Scheme 5. Synthesis of compound 18. Chem. Eur. J. 2015, 21, 10466 – 10471
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Full Paper Properties of dendrimer 26 The structure of dendrimer 26 in THF solution was investigated with small-angle X-ray scattering (SAXS) for scattering vectors in the range of 0.15 to 7 nm¢1. This gives information about external and internal structural features ranging from 21 to 0.5 nm. The detected scattering pattern, measured at concentrations of 2 and 5 % (w/w), is typical for non-interacting nanoparticles. Tentatively, we applied a spherical model for data interpretation and found that the experimental curve shape is surprisingly well-reproduced for q-values smaller than 1.4 nm¢1, whereas deviations at higher q-values are obvious (see Figure 3). The derived sphere radius for dendrimer 26 is R = (2.72 0.05) nm, which corresponds to a radius of gyration of Rg = (2.11 0.04) nm and a volume of 84.2 nm3. When taking the molecular weight of 6303.9 g mol¢1 into account this results in an apparent dendrimer density of 0.12 g cm¢3 within Scheme 6. Synthesis of compound 20; i) TBAF, THF, ii) 5, Cu/C, DCM.
Scheme 7. Synthesis of branch 25; i) TsOH, DMF/benzene, ii) Cu/C, Et3N, DCM, 16, iii) NaN3/DMF.
Figure 3. SAXS curve of dendrimer 26 and curve fits with a sphere and Dozier star model (solid black, dash-dotted red, and solid blue curve, respectively). The radius of the sphere model is 2.72 nm. The Guinier term of the Dozier star model has an Rg of 2.33 nm (dotted green curve). The mass fractal term has an internal correlation length of x = 0.42 nm (dashed green curve). The scaling of the intensity with q¢2 for q > 1.8 nm¢1 is indicated by a straight line.
Scheme 8. Synthesis of dendrimer 26. Chem. Eur. J. 2015, 21, 10466 – 10471
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Full Paper the particle. Such low density indicates that the dendrimer 26 is highly swollen with solvent. We estimate a volume fraction of 14 % for the dendrimer within the nanoparticle if we approximate that the dendrimer has the same density as THF (0.889 g mol¢1). It is surprising that a globular structure has such a low density. We expect therefore an inhomogeneous internal structure, which should contribute to the scattering pattern at high qvalues. Indeed, the intensity scales with q¢2 for q > 1.7 nm¢1 as indicated by the straight line in Figure 3. Such scaling law is typical for a mass fractal. Therefore, a model has to be utilized that combines features of an overall spherical structure (for distances larger than p/ 1.4 nm¢1 = 2.2 nm) and a fractal internal structure (for distances smaller than p/1.7 nm¢1 = 1.8 nm). A suitable model that combines these two features has been derived by Dozier et al.[25] for interpretation of the colloidal nature of star polymers. The scattering function I(q) of the Dozier model is given by the following equation IðqÞ ¼ I0 expð¢R2g q2 =3Þ þ
4pa sinðm arctanðxqÞÞ GðmÞ xq ð1 þ ðxaÞ2 Þm=2
ð1Þ
The first summand is the Guinier term with a scaling factor I0 and a radius of gyration Rg. The second summand describes a mass fractal with a scaling factor a, a correlation length inside the star x, and m = 1/u¢1. The u is the Flory exponent, which is 3/5 in a good solvent and 1/2 in a theta solvent. A best fit of the Dozier models results in Rg = (2.33 0.05) nm. This corresponds to an apparent sphere radius of R = (3.01 0.06) nm with a volume of 114 nm3, which is slightly larger but consistent with the sphere model. The internal structure correlation length is x = (0.42 0.05) nm. This value is consistent with the size of the oligospiroketal building blocks. The u was held constant at 0.5 during fitting to avoid unambiguous results, that is, theta solvent conditions. A model-free data evaluation procedure for the calculation of the radial density profile as developed by Mittelbach and Glatter[26] was used to test our proposed structural model. The resulting continuous density profile as measured from the center of the particle shows a stepwise decrease of the electron density towards the periphery (Figure 4). In the first step,
Figure 4. Cross section density profile of the dendrimer 26 as calculated with the program DECON.[26] Chem. Eur. J. 2015, 21, 10466 – 10471
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the density decreases slowly from 1.0 to 0.5 between 1 and 2 nm. In a second, steeper step the density decreases from 0.5 to 0 between 2.6 and 3.2 nm. Such characteristics are in agreement with a spherical structure and the Dozier star model. In addition, the comparison of simulated SAXS curves, produced from snap shots during the Molecular Dynamic (MD) simulation of dendrimer 26 with the measured SAXS data, were performed (see Figure 5). Therein, the arrow points from
Figure 5. Comparison of simulated SAXS curves produced from snap shots during the MD simulation with the measured SAXS data. The arrow points to the direction of the simulation structures from the unfolded structure A via the semi-folded structures B to E to the finally folded structure F.
simulation of the unfolded structure A via the semi-folded structures B to E to the finally folded structure F. The radii of gyration were 2.81 nm (A), 1.99 nm (B), 2.16 nm (C), 1.88 nm (D), 1.64 nm (E), and 1.32 nm (F). Therefore, when considering the Rg values, the semi-folded structure (C) has the best match with the experimental value of 2.33 nm. On the other hand, the steep decay of the experimental curve at around q = 1 nm¢1 indicates a better-defined structure than seen in the MD simulations. This may be produced by a back-folding of segments, in the most efficient way by folding back the alkyl chains. To summarize the SAXS results: a back-folding of segments is very likely, in such a way that a spherical object is formed with a clearly defined surface towards the particle surroundings. The surface is smooth, but the internal structure resem-
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Full Paper bles a mass-fractal[27] with random-walk statistics like a Gaussian polymer chain. A more detailed discussion about chemical and fractal structure and properties is given elsewhere.[28] [5]
Conclusion For the synthesis of dendrimers with OSK building blocks we developed several building blocks, which can be subdivided in a core unit (CU, 1), branching units (BU, 5, 23) and OSK rods (10, 16). These building blocks are appropriately functionalized to build up the dendrimers by a CuAAC. Based on the model system 17 different catalysts were examined and the best results were obtained with the Cu/C catalyst.[22] The synthesis of dendrimers by a divergent approach, that is, by repetitive construction starting with a core unit (CU), has proven to be a difficult task. The main reasons for this are incomplete click reactions and a limited stability of the TMS protecting group of terminal alkynes under the click conditions. As a result, inseparable mixtures were obtained. The convergent approach, that is, the separate synthesis of a branch and subsequent coupling between branch and CU, was substantially more successful. Thus, the dendrimer 26 could be obtained with satisfactory yield by click reaction between branch 25 and CU 1. The structure of 26 was investigated by SAXS and revealed a globular structure with surprisingly low density (0.12 g cm¢3). A comparison of the SAXS results with those of MD simulations clearly proves a partially folded structure. We assume that the terminal alkyl chains largely back-folded but the OSK rods maintain an internal structure, which could be considered as mass fractal. Keywords: click chemistry · dendrimers · molecular rods · oxygen heterocycles · SAXS [1] D. Astruc, E. Boisselier, C. Ornelas, Chem. Rev. 2010, 110, 1857 – 1959. [2] For selected books about dendrimers, see: a) A. Caminade, Dendrimers: Towards Catalytic, Material and Biomedical Uses, Wiley-VCH, Weinheim, 2011; b) L. H. Gade, Dendrimer Catalysis (Topics in Organometallic Chemistry), Springer, Heidelberg, 2006; c) Y. Cheng, Dendrimer-Based Drug Delivery Systems: From Theory to Practice, Wiley-VCH, Weinheim, 2012; d) D. A. Tomalia, J. B. Christensen, U. Boas, Dendrimers, Dendrons, and Dendritic Polymers: Discovery, Applications, and the Future, Cambridge University Press, Cambridge, 2012; e) U. Boas, J. B. Christensen, P. M. H. Heegaard, Dendrimers in Medicine and Biotechnology: New Molecular Tools, Royal Society of Chemistry, Cambridge, 2006. [3] X. Wang, L. Guerrand, B. Wu, X. Li, L. Boldon, W. Chen, L. Liu, Polymers 2012, 4, 600 – 616. [4] Reviews on molecular rods: a) J. M. Tour, Chem. Rev. 1996, 96, 537 – 553; b) P. F. H. Schwab, M. D. Levin, J. Michl, Chem. Rev. 1999, 99, 1863 –
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[6] [7] [8]
[9]
[10] [11] [12]
[13] [14] [15]
[16]
[17] [18] [19] [20] [21] [22] [23] [24]
[25] [26] [27] [28]
1933; c) M. D. Levin, P. Kaszynski, J. Michl, Chem. Rev. 2000, 100, 169 – 234; d) J. M. Tour, Acc. Chem. Res. 2000, 33, 791 – 804; e) P. F. H. Schwab, J. R. Smith, J. Michl, Chem. Rev. 2005, 105, 1197 – 1279; f) N. Sakai, J. Mareda, S. Matile, Acc. Chem. Res. 2005, 38, 79 – 87. a) K. O. Kim, T. Choi, Macromolecules 2013, 46, 5905 – 5914; b) L. L. Miller, J. S. Schlechte, B. Zinger, C. J. Burrell, Chem. Mater. 2002, 14, 5081 – 5089. P. Wessig, K. Mçllnitz, C. Eiserbeck, Chem. Eur. J. 2007, 13, 4859 – 4872. P. Wessig, K. Mçllnitz, J. Org. Chem. 2008, 73, 4452 – 4457. P. Mìller, J. Nikolaus, S. Schiller, A. Herrmann, K. Mçllnitz, S. Czapla, P. Wessig, Angew. Chem. Int. Ed. 2009, 48, 4433 – 4435; Angew. Chem. 2009, 121, 4497 – 4500. J. Nikolaus, S. Czapla, K. Mçllnitz, C. T. Hçfer, A. Herrmann, P. Wessig, P. Mìller, Biochim. Biophys. Acta (BBA) - Biomembranes 2011, 1808, 2781 – 2788. P. Wessig, K. Mçllnitz, J. Org. Chem. 2012, 77, 3907 – 3920. A. Techen, S. Czapla, K. Mçllnitz, D. Budach, P. Wessig, M. Kumke, Helv. Chim. Acta 2013, 96, 2046 – 2067. C. Grimm, T. Meyer, S. Czapla, J. Nikolaus, H. A. Scheidt, A. Vogel, A. Herrmann, P. Wessig, D. Huster, P. Mìller, Chem. Eur. J. 2013, 19, 17 2703 – 17 2710. P. Wessig, M. Gerngroß, S. Pape, P. Bruhns, J. Weber, RSC Adv. 2014, 4, 31123 – 31129. J. Lahann, Click Chemistry for Biotechnology and Materials Science, Wiley-VCH, Weinheim, 2009. For selected publications about synthesis of dendrimers using CuAAC, see: a) L. Liang, D. Astruc, Coord. Chem. Rev. 2011, 255, 2933 – 2945; b) M. J. Robb, C. J. Hawker, in Synthesis of Polymers: New Structures and Methods (Eds.: D. A. Schluter, C. Hawker, J. Sakamoto), Wiley-VCH, Weinheim, 2012, pp. 923 – 971; c) N. El Brahmi, S. El Kazzouli, S. Mignani, M. Bousmina, J. P. Majoral, Tetrahedron 2013, 69, 3103 – 3133. F. G. Calvo-Flores, J. Isac-Garca, F. Hernndez-Mateo, F. P¦rez-Balderas, J. A. Calvo-Asn, E. Sanch¦z-Vaquero, F. Santoyo-Gonzlez, Org. Lett. 2000, 2, 2499 – 2502. A. Gheorghe, T. Chinnusamy, E. Cuevas-Yanez, P. Hilgers, O. Reiser, Org. Lett. 2008, 10, 4171 – 4174. V. Aucagne, D. A. Leigh, Org. Lett. 2006, 8, 4505 – 4507. T. Tsunoda, M. Suzuki, R. Noyori, Tetrahedron Lett. 1980, 21, 1357 – 1358. L. Liang, J. Ruiz, D. Astruc, Adv. Synth. Catal. 2011, 353, 3434 – 3450. B. H. Lipshutz, B. R. Taft, Angew. Chem. Int. Ed. 2006, 45, 8235 – 8238; Angew. Chem. 2006, 118, 8415 – 8418. V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2596 – 2599; Angew. Chem. 2002, 114, 2708 – 2711. P. Wessig, R. Merkel, P. Mìller, Beilstein J. Org. Chem. 2015, 11, 74 – 84. M. Ortega-MuÇoz, F. Perez-Balderas, J. Morales-Sanfrutos, F. HernandezMateo, J. Isac-Garcia, F. Santoyo-Gonzalez, Eur. J. Org. Chem. 2009, 2009, 2454 – 2473. W. D. Dozier, J. S. Huang, L. J. Fetters, Macromolecules 1991, 24, 2810 – 2814. R. Mittelbach, O. Glatter, J. Appl. Crystallogr. 1998, 31, 600 – 608. B. Hammouda, Macromol. Theory Simul. 2012, 21, 372 – 381. G. R. Newkome, C. D. Shreiner, Polymer 2008, 49, 1 – 173.
Received: April 9, 2015 Published online on June 11, 2015
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Dendrimers with Oligospiroketal (OSK) Building Blocks: Synthesis and Properties Pablo Wessig,*[a] Dennis Budach,[a] and Andreas F. Thìnemann[b] Dedicated to Professor Bernd Giese on the occasion of his 75th birthday
Abstract: The development of novel dendrimers containing oligospiroketal (OSK) rods as building blocks is described. The linkage between the core unit (CU), branching units (BU), and OSK rods relies on the CuAAC reaction between terminal alkynes and azides. Two different strategies of dendrimer synthesis were investigated and it was found that the
Introduction Dendrimers are tree-like large molecules, which are characterized by repetitively occurring branches.[1, 2] In contrast to polymers they are monodisperse and, in most cases, highly symmetric. In recent decades, countless publications about dendrimers have been released and meanwhile they have found widespread application in material science,[2a, d] catalysis,[2a, b] and pharmaceutical chemistry (especially in drug delivery).[2c, e] The physical and biological properties of dendrimers depend on the conformational rigidity of the individual building blocks. This applies especially to the apparent size of dendrimer molecules, derivable from their hydrodynamic radius.[3] Dendrimers consisting of rather flexible elements tend towards entanglement and back-folding and thus minimize their entropy. This can be countered by utilizing molecular rods[6] as additional building blocks. Admittedly, this approach has seldom been used and, herein, we wish to report on investigations on the synthesis and outstanding properties of dendrimers bearing rigid rods as structural elements.[7] Several years ago we developed a new class of molecular rods whose key elements are ketal structures. We therefore called these rods oligospiroketal (OSK) rods.[6–13] The backbone of these rods consists of spirocyclically joined 1,3-dioxane and [a] Prof. Dr. P. Wessig, Dr. D. Budach Institut fìr Chemie, Universitt Potsdam Karl-Liebknecht-Str. 24–25, 14476 Potsdam (Germany) Fax: (+ 49) 3319775065 E-mail: [email protected] Homepage: http://ag-wessig.chem.uni-potsdam.de [b] Prof. Dr. A. F. Thìnemann Bundesanstalt fìr Materialforschung und -prìfung Unter den Eichen 87, 12205 Berlin (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201501386. Chem. Eur. J. 2015, 21, 10466 – 10471
convergent approach is clearly superior to the divergent one. SAXS measurements and MD simulations indicate that the obtained dendrimer features a globular structure with very low density. Obviously, the OSK rods stabilize a rather loose mass-fractal structure.
cyclohexane rings. Terminal functionalities are introduced, for example, by piperidine-4-one derivatives. Meanwhile, we disclosed several applications of OSK rods in biological systems,[8, 9, 12] as rigid spacers[11] and as building blocks in porous materials.[13] In general, dendrimers consist of a core unit with three or more connecting points, branching units, and terminal functionalities. A highly efficient coupling reaction is the decisive precondition for the successful synthesis of a dendrimer. Several coupling reactions have been applied in this context, in which the copper-catalyzed [3+ +2] cycloaddition between azides and terminal alkynes (copper-catalyzed alkyne-azide cycloaddition, CuAAC, click-reaction)[14] has been frequently employed.[15] Therefore, we also used this powerful method in this work.
Results and Discussion Building blocks As mentioned above, all dendrimers exhibit a multivalent core unit (CU). Because the CuAAC between terminal alkynes and azides was supposed to be the build-up reaction, we choose the tetrapropargyl ether of pentaerythritol (1) as the Figure 1. Core unit (CU) 1. core unit (Figure 1).[16] The required branching units (BU) should possess the following structural features: an azide and at least two terminal alkynes, protected with trimethylsilyl groups. The synthesis of the first BU commences with alcohol 2, which is known in the literature[17] and is readily available from reactions with methyl gallate. The alkyne moieties were protected with TMS groups. The resulting alcohol 3 was converted to the azide 5 in two steps
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Scheme 3. Synthesis of OSK rod 16; i) TMSCl/NaH, toluene, ii) lauroyl chloride/DIPEA, DCM, iii) (COCl)2/DMSO, DCM, iv) TMSOTf, DCM, v) NaN3, DMF; R = C11H23. Scheme 1. Synthesis of branching unit 5; i) BuLi/TMSCl, THF, ii) CBr4/PPh3, DMF, iii) NaN3, DMF.
to Noyori’s method[19] using the bis-trimethylsilyl-ether 12, which was prepared from the known diol 11.[9] Finally, the chloroacetyl group was converted into an azidoacetyl group with quantitative yield giving the rod 16 (Scheme 3). Divergent approach There are fundamentally two ways to construct a dendrimer. The divergent approach starts with CU and builds up the dendrimer by repetitive introduction of BUs or alternating introduction of BUs and extension building blocks. We initially pursued this approach. Due to the pivotal relevance of the CuAAC in our dendrimer synthesis we first undertook an optimization of the click conditions by means of the CU 1 and the BU 5 (Scheme 4).
Scheme 2. Synthesis of OSK rod 10; i) 4-nitrophenyl 3-(trimethylsilyl)-2-propynyl carbonate,[18] DCM, ii) (COCl)2/DMSO, DCM, iii) 1. NaH,TMSCl, 2. TMSOTf, DCM.
and with excellent yields (Scheme 1, a second BU was used in the convergent approach, see below). There are two ways to incorporate OSK rods into the dendrimers: 1) as an extending unit between CUs and BUs or between two BUs, or 2) as terminal units at the periphery of the dendrimer. For both approaches we developed appropriately functionalized OSK rods. It should be noted that we used trispiranes as model rods to reduce the synthetic effort. The synthetic route to the first type of rods is outlined in Scheme 2. 4Hydroxypiperidine 6 is first converted to the TMS-protected propargyl carbamate 7, which was then oxidized to the ketone 8. Reaction of 8 with the previously developed azido-diol 9[9] using the method of double activation[8] afforded the OSK rod 10 (Scheme 2). Similarly, we prepared the terminal OSK rods. For this purpose 4-hydroxypiperidine 6 was first lauroylated for solubility enhancement of the dendrimers and then oxidized to ketone 14. The construction of the trispirane 15 took place according Chem. Eur. J. 2015, 21, 10466 – 10471
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Scheme 4. CuAAC reaction between 1 and 5 (for conditions, see Table 1).
For this purpose we investigated three different catalyst systems, which are summarized in Table 1. The resulting product mixtures were analyzed with MALDI-TOF mass spectrometry
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Full Paper Table 1. Click conditions A–C. Entry
Catalyst
Conditions
Ref.
A B
CuBr/TREN-Bn6[a] Cu/C
[20] [21]
C
CuSO4/ascorbate
4 equiv cat., toluene, reflux, 24 h 4 equiv cat., 1 equiv Et3N, DCM, RT, 24 h 8 equiv cat., H2O/tBuOH/DCM, 24 h
[a] TREN-Bn6 = hexabenzyl-tris(aminoethyl)amine.
[22]
After the catalyst optimization we applied these settings to the click reaction of CU 1 and rod 10. Once again we obtained the desired fourfold substituted product 18 beside nearly the same amounts of threefold substituted product (Scheme 5). Moreover, we detected signals in the MALDI-TOF mass spectrum, which could be explained by the cleavage of one TMS group in 18, followed by a repeated click reaction with 10 (see the Supporting Information). Although the mixture containing 18 could not be separated, we continued with the dendrimer synthesis. After cleavage of TMS groups giving 19 the click reaction with BU 5 using Cu/C catalyst was performed. The target compound 20 could indeed be detected in the mass spectra but only as minor component (Scheme 6). Subsequent attempts to convert 20 to a dendrimer were not successful. Clearly, it is not possible to prepare dendrimers by this approach due to a) incomplete click reactions and b) partial cleavage of TMS protecting groups during the click reaction followed by an undesired repeated click reaction. Convergent approach
Figure 2. MALDI-TOF mass spectra of 17 obtained with catalysts A–C (4x = blue symbols, 3x = red symbols, 2x = green symbols).
After the rather sobering experience with the divergent approach we now turned to the convergent approach. The deciding feature of this approach is that at first a “branch” is prepared, which is then connected with the core unit in the final step of the dendrimer synthesis. The branch synthesis commences with two building blocks: the piperidin-4-one 21[9] and the diol 22.[24] After acetalization between these compounds to spirane 23, a click reaction with rod 16 was performed. The resulting chloroacetyl derivative 24 was converted into the azide 25 in the final step (Scheme 7). To our delight, the branch building block 25 could be successfully coupled with the CU 1 to give the dendrimer 26 with 38 % yield. It is noteworthy that, in contrast to the product mixtures obtained with the divergent approach, 26 could be easily purified by simple flash chromatography (Scheme 8).
and a comparison of the corresponding spectra is depicted in Figure 2. In all cases we detected the desired product 17 with fourfold cycloaddition (blue symbols) of 5 to 1 (m/z = 2332, ^). The product peak is accompanied either by a peak of the Na + adduct (m/z = 2355, *, cond. A), the K + adduct (m/z = 2371, &, cond. B), the adduct with [2Cu] + (m/z = 2458, !, cond. B) or the adduct with Cu + (m/z = 2397, N, cond. C). Furthermore, with catalysts A and C, we also observed the analogous signals of threefold (red symbols) and twofold substituted products. In the MALDI-TOF mass spectrum of the mixture obtained with catalyst A we also observed peaks at 1536, 2050 and 2563 Da, which could be assigned to adducts with [3Cu + K] + (fl). To sum up, the highest selectivity was achieved with the Cu/C catalyst B. It should be noted that we obtained similar results very recently in connection with the synthesis of molecular rods.[23] Scheme 5. Synthesis of compound 18. Chem. Eur. J. 2015, 21, 10466 – 10471
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Full Paper Properties of dendrimer 26 The structure of dendrimer 26 in THF solution was investigated with small-angle X-ray scattering (SAXS) for scattering vectors in the range of 0.15 to 7 nm¢1. This gives information about external and internal structural features ranging from 21 to 0.5 nm. The detected scattering pattern, measured at concentrations of 2 and 5 % (w/w), is typical for non-interacting nanoparticles. Tentatively, we applied a spherical model for data interpretation and found that the experimental curve shape is surprisingly well-reproduced for q-values smaller than 1.4 nm¢1, whereas deviations at higher q-values are obvious (see Figure 3). The derived sphere radius for dendrimer 26 is R = (2.72 0.05) nm, which corresponds to a radius of gyration of Rg = (2.11 0.04) nm and a volume of 84.2 nm3. When taking the molecular weight of 6303.9 g mol¢1 into account this results in an apparent dendrimer density of 0.12 g cm¢3 within Scheme 6. Synthesis of compound 20; i) TBAF, THF, ii) 5, Cu/C, DCM.
Scheme 7. Synthesis of branch 25; i) TsOH, DMF/benzene, ii) Cu/C, Et3N, DCM, 16, iii) NaN3/DMF.
Figure 3. SAXS curve of dendrimer 26 and curve fits with a sphere and Dozier star model (solid black, dash-dotted red, and solid blue curve, respectively). The radius of the sphere model is 2.72 nm. The Guinier term of the Dozier star model has an Rg of 2.33 nm (dotted green curve). The mass fractal term has an internal correlation length of x = 0.42 nm (dashed green curve). The scaling of the intensity with q¢2 for q > 1.8 nm¢1 is indicated by a straight line.
Scheme 8. Synthesis of dendrimer 26. Chem. Eur. J. 2015, 21, 10466 – 10471
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Full Paper the particle. Such low density indicates that the dendrimer 26 is highly swollen with solvent. We estimate a volume fraction of 14 % for the dendrimer within the nanoparticle if we approximate that the dendrimer has the same density as THF (0.889 g mol¢1). It is surprising that a globular structure has such a low density. We expect therefore an inhomogeneous internal structure, which should contribute to the scattering pattern at high qvalues. Indeed, the intensity scales with q¢2 for q > 1.7 nm¢1 as indicated by the straight line in Figure 3. Such scaling law is typical for a mass fractal. Therefore, a model has to be utilized that combines features of an overall spherical structure (for distances larger than p/ 1.4 nm¢1 = 2.2 nm) and a fractal internal structure (for distances smaller than p/1.7 nm¢1 = 1.8 nm). A suitable model that combines these two features has been derived by Dozier et al.[25] for interpretation of the colloidal nature of star polymers. The scattering function I(q) of the Dozier model is given by the following equation IðqÞ ¼ I0 expð¢R2g q2 =3Þ þ
4pa sinðm arctanðxqÞÞ GðmÞ xq ð1 þ ðxaÞ2 Þm=2
ð1Þ
The first summand is the Guinier term with a scaling factor I0 and a radius of gyration Rg. The second summand describes a mass fractal with a scaling factor a, a correlation length inside the star x, and m = 1/u¢1. The u is the Flory exponent, which is 3/5 in a good solvent and 1/2 in a theta solvent. A best fit of the Dozier models results in Rg = (2.33 0.05) nm. This corresponds to an apparent sphere radius of R = (3.01 0.06) nm with a volume of 114 nm3, which is slightly larger but consistent with the sphere model. The internal structure correlation length is x = (0.42 0.05) nm. This value is consistent with the size of the oligospiroketal building blocks. The u was held constant at 0.5 during fitting to avoid unambiguous results, that is, theta solvent conditions. A model-free data evaluation procedure for the calculation of the radial density profile as developed by Mittelbach and Glatter[26] was used to test our proposed structural model. The resulting continuous density profile as measured from the center of the particle shows a stepwise decrease of the electron density towards the periphery (Figure 4). In the first step,
Figure 4. Cross section density profile of the dendrimer 26 as calculated with the program DECON.[26] Chem. Eur. J. 2015, 21, 10466 – 10471
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the density decreases slowly from 1.0 to 0.5 between 1 and 2 nm. In a second, steeper step the density decreases from 0.5 to 0 between 2.6 and 3.2 nm. Such characteristics are in agreement with a spherical structure and the Dozier star model. In addition, the comparison of simulated SAXS curves, produced from snap shots during the Molecular Dynamic (MD) simulation of dendrimer 26 with the measured SAXS data, were performed (see Figure 5). Therein, the arrow points from
Figure 5. Comparison of simulated SAXS curves produced from snap shots during the MD simulation with the measured SAXS data. The arrow points to the direction of the simulation structures from the unfolded structure A via the semi-folded structures B to E to the finally folded structure F.
simulation of the unfolded structure A via the semi-folded structures B to E to the finally folded structure F. The radii of gyration were 2.81 nm (A), 1.99 nm (B), 2.16 nm (C), 1.88 nm (D), 1.64 nm (E), and 1.32 nm (F). Therefore, when considering the Rg values, the semi-folded structure (C) has the best match with the experimental value of 2.33 nm. On the other hand, the steep decay of the experimental curve at around q = 1 nm¢1 indicates a better-defined structure than seen in the MD simulations. This may be produced by a back-folding of segments, in the most efficient way by folding back the alkyl chains. To summarize the SAXS results: a back-folding of segments is very likely, in such a way that a spherical object is formed with a clearly defined surface towards the particle surroundings. The surface is smooth, but the internal structure resem-
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Full Paper bles a mass-fractal[27] with random-walk statistics like a Gaussian polymer chain. A more detailed discussion about chemical and fractal structure and properties is given elsewhere.[28] [5]
Conclusion For the synthesis of dendrimers with OSK building blocks we developed several building blocks, which can be subdivided in a core unit (CU, 1), branching units (BU, 5, 23) and OSK rods (10, 16). These building blocks are appropriately functionalized to build up the dendrimers by a CuAAC. Based on the model system 17 different catalysts were examined and the best results were obtained with the Cu/C catalyst.[22] The synthesis of dendrimers by a divergent approach, that is, by repetitive construction starting with a core unit (CU), has proven to be a difficult task. The main reasons for this are incomplete click reactions and a limited stability of the TMS protecting group of terminal alkynes under the click conditions. As a result, inseparable mixtures were obtained. The convergent approach, that is, the separate synthesis of a branch and subsequent coupling between branch and CU, was substantially more successful. Thus, the dendrimer 26 could be obtained with satisfactory yield by click reaction between branch 25 and CU 1. The structure of 26 was investigated by SAXS and revealed a globular structure with surprisingly low density (0.12 g cm¢3). A comparison of the SAXS results with those of MD simulations clearly proves a partially folded structure. We assume that the terminal alkyl chains largely back-folded but the OSK rods maintain an internal structure, which could be considered as mass fractal. Keywords: click chemistry · dendrimers · molecular rods · oxygen heterocycles · SAXS [1] D. Astruc, E. Boisselier, C. Ornelas, Chem. Rev. 2010, 110, 1857 – 1959. [2] For selected books about dendrimers, see: a) A. Caminade, Dendrimers: Towards Catalytic, Material and Biomedical Uses, Wiley-VCH, Weinheim, 2011; b) L. H. Gade, Dendrimer Catalysis (Topics in Organometallic Chemistry), Springer, Heidelberg, 2006; c) Y. Cheng, Dendrimer-Based Drug Delivery Systems: From Theory to Practice, Wiley-VCH, Weinheim, 2012; d) D. A. Tomalia, J. B. Christensen, U. Boas, Dendrimers, Dendrons, and Dendritic Polymers: Discovery, Applications, and the Future, Cambridge University Press, Cambridge, 2012; e) U. Boas, J. B. Christensen, P. M. H. Heegaard, Dendrimers in Medicine and Biotechnology: New Molecular Tools, Royal Society of Chemistry, Cambridge, 2006. [3] X. Wang, L. Guerrand, B. Wu, X. Li, L. Boldon, W. Chen, L. Liu, Polymers 2012, 4, 600 – 616. [4] Reviews on molecular rods: a) J. M. Tour, Chem. Rev. 1996, 96, 537 – 553; b) P. F. H. Schwab, M. D. Levin, J. Michl, Chem. Rev. 1999, 99, 1863 –
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Received: April 9, 2015 Published online on June 11, 2015
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