Amide POSS from OAS Salts: Base Choice and Cage Integrity

Amide derivatives of octa(3-aminopropyl)silsesquioxane (OAS-POSS) rank among the most useful organic–inorganic hybrids that can be assembled on a cubic siloxane core. Conventional routes to these compounds rely on carboxylic acids activated by coupling agents such as DCC, or on acid anhydrides, and rarely exceed roughly 60 % yield. Janeta and co-workers (Chem. – Eur. J. 2014, 20, 15966–15974) demonstrated that acyl chlorides offer a decisively better alternative, furnishing homosubstituted amide-POSS in yields approaching 95 % while leaving the (RSiO_3/2)₈ framework intact.

This post focuses on why ionic OAS-POSS precursors resist cage opening and how the choice of base governs the outcome of amidation. The full synthetic scope, spectroscopic characterization, and nanoparticle formation are described in Amide POSS in 95% Yield from OAS Salts and Acyl Chlorides.

Ionic precursors as stable scaffolds

Neutral octa(3-aminopropyl)silsesquioxane is inconvenient to store, because it evolves continuously in solution and is prone to opening of the cage. Three crystalline ammonium salts were therefore prepared in a one-step hydrolytic condensation of (3-aminopropyl)triethoxysilane (APTES) with hydrochloric acid (3.6 equiv), trifluoromethanesulfonic acid (1.5 equiv) or trifluoroacetic acid (1.5 equiv), affording [OAS-POSS-NH₃]Cl (1), [OAS-POSS-NH₃]CF₃SO₃ (2) and [OAS-POSS-NH₃]CF₃COO (3), respectively. The chloride salt crystallizes slowly and requires four weeks at 25 °C to reach 45 % yield, whereas the triflate salt is isolated in 95 % yield within a few hours. The trifluoroacetate was set aside because it forms a strongly hygroscopic glass that is difficult to handle.

Each salt displays a single symmetrical ²⁹Si resonance near δ = −66.5 ppm, the value expected for a cubic T₈ cage containing only one type of silicon environment, and the asymmetric Si–O–Si stretching band appears at 1116, 1138 and 1132 cm⁻¹ for 1, 2 and 3. These siloxane absorptions are markedly narrower than those recorded for analogous hybrid materials obtained by conventional sol–gel routes, which reflects the high symmetry of the isolated products. Transmission electron microscopy combined with selected-area electron diffraction revealed particles in the 5–10 nm range for 1 and 2, whereas 3 proved to be a shapeless product.

Cage opening under hydrous conditions

Generation of the free amine demands strictly anhydrous conditions. When a 5 % aqueous solution of sodium hydrogencarbonate was added to 1 in a controlled manner, the cubic core opened and the open-cage species 5 was formed, which was stabilized as its hydrochloride. Its ¹H NMR spectrum contains a broad silanol signal at δ = 3.64 ppm that gives an NOE cross-peak with the ammonium resonance, and the ²⁹Si spectrum shows two signals of equal intensity at δ = −65.90 and −66.65 ppm, assigned respectively to silicon atoms carrying three Si–O–Si linkages and to those carrying two Si–O–Si units together with one Si–OH group. The ν(Si–OH) vibration is observed at 990 cm⁻¹. The opening is initiated by attack of the aliphatic amine nitrogen at silicon rather than by hydroxide, a conclusion supported by the observation that no opening occurs once the amine has been converted into an amide.

The decisive role of the base

Benzoylation was first attempted under classical Schotten–Baumann conditions with sodium hydroxide, but this base proved far too strong and destroyed the polyoctasilsesquioxane core. An aqueous solution of sodium hydrogencarbonate, although considerably weaker, was likewise unsatisfactory. Only triethylamine allowed the siloxane framework to survive. An excess of this weak base fulfills two functions at once: it liberates the free amine 4 in situ from the ammonium salt, and it neutralizes the hydrogen chloride released as the acyl chloride reacts.

Scope of the amidation

The reactions were conducted in anhydrous N,N-dimethylformamide at 0 °C. Benzoyl chloride and its 4-nitro and 4-fluoro derivatives were employed with 8.8 equiv of acyl chloride and 18.5 equiv of triethylamine to give 9, 6 and 8, while hexanoyl chloride required 16.3 equiv together with 26.4 equiv of the base to give the hexanoamide 10. Yields improved appreciably when the reaction mixture was left in a freezer overnight. The triflate salt 2 consistently outperformed the chloride, and for the 4-nitrobenzamide 6 the yield reached 97 %. The crude products were precipitated into cold 1 M aqueous hydrochloric acid, then washed with saturated sodium hydrogencarbonate and with water before drying in vacuo.

A clear distinction emerged between aromatic and aliphatic acyl chlorides. With an excess of aryl acyl chloride no tertiary amide was detected, whereas the reaction with hexanoyl chloride produced a mixture of species differing in the number of attached C₆H₁₁O groups, and two successive passes through a flash silica column were needed to isolate the homoocta-substituted material. The absence of residual primary amine in every product was verified with ninhydrin, none of the tests producing the characteristic violet color. The 4-aminobenzamide derivative 7 was obtained separately by reducing the nitro compound 6 with hydrogen generated in situ from zinc. Notably, 7 tolerates sodium hydroxide during workup without loss of the cubic core, as confirmed by a single ²⁹Si resonance at δ = −68.0 ppm.

Spectroscopic and thermal characterization

All amide-POSS were characterized by FTIR spectroscopy, by multinuclear ¹H, ¹³C and ²⁹Si NMR spectroscopy and by mass spectrometry, the last of which confirmed complete octasubstitution. For 6 the amide group gives rise to bands at 1649, 1547 and 1301 cm⁻¹, assigned to ν(C=O), δ(N–H) and ν(C–N), with ν(Si–O–Si) at 1222 cm⁻¹. The siloxane absorption is unusually narrow, an observation of practical importance because it indicates a well-defined and highly symmetric cage. No silanol groups were detected in any of the amide derivatives, and their siloxane networks survive alkaline media, which the authors attribute to the steric bulk of the side chains.

Thermogravimetric analysis in air revealed decomposition in two stages. The side chains are extruded first, and above 400 °C the siloxane cage converts to silica, as confirmed by infrared spectroscopy of the residue. The unsubstituted benzamide 9 loses its side chains at the comparatively low temperature of 165 °C, whereas substitution of the aryl ring in the para position raises this value substantially, reaching 396 °C for the 4-fluoro derivative 8. For comparison, the chloride salt 1 decomposes at 314 °C and the triflate 2 at 428 °C.

Formation of well-separated nanoparticles

Compounds 6–10 were dissolved in dimethyl sulfoxide, precipitated with deionized water, centrifuged at 5800 rpm and sonicated in methanol. This treatment furnished particles approximately 5 nm in diameter that are spherical for the aryl-substituted derivatives and, importantly, remain well separated instead of forming agglomerates. The hexanoamide 10 was the sole exception, adopting a fibrous morphology that reflects the flexible carbon side chains attached to the core. The composition of the particles was verified by energy-dispersive X-ray spectroscopy and their crystallinity by powder X-ray diffraction and selected-area electron diffraction.

Significance

Salts of OAS-POSS bearing chloride or triflate counterions therefore constitute convenient, air-stable starting materials for the controlled assembly of well-defined homoocta-amido-functionalized silsesquioxanes carrying either alkyl or aryl substituents, and careful control of the reaction conditions suppresses the formation of open-cage by-products. Because the resulting nanohybrids combine an organic shell of essentially arbitrary composition with the thermal, mechanical and chemical robustness of the siloxane core, they are attractive candidates for chromatographic column packings and for drug delivery systems, in which role they may serve as functional replacements for modified silica. The drug-carrier concept was developed further in a subsequent study, in which benzamide-POSS platforms were loaded with acetaminophen and ibuprofen and shown to release them under physiological conditions at pH 7.40.

References

(1) Janeta, M.; John, Ł.; Ejfler, J.; Szafert, S. High-Yield Synthesis of Amido-Functionalized Polyoctahedral Oligomeric Silsesquioxanes by Using Acyl Chlorides. Chem. – Eur. J. 2014, 20, 15966–15974. DOI: 10.1002/chem.201404153

(2) John, Ł.; Malik, M.; Janeta, M.; Szafert, S. First Step towards a Model System of the Drug Delivery Network Based on Amide-POSS Nanocarriers. RSC Adv. 2017, 7, 8394–8401. DOI: 10.1039/C6RA26330E

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This post has its own persistent identifier. Please use the DOI below when citing it.

Polyhedral Oligomeric Silsesquioxane (POSS) Chemistry. (2018). Amide POSS from OAS Salts: Base Choice and Cage Integrity. https://doi.org/10.59350/5yvs8-2e619