Unveiling the Structure and Reactivity of Fatty-Acid Based (Nano)materials Thanks to Efficient and Scalable ¹⁷O and ¹⁸O-Isotopic Labeling Schemes

Abstract

Fatty acids are ubiquitous in biological systems and widely used in materials science, including for the formulation of drugs and the surface-functionalization of nanoparticles. However, important questions regarding the structure and reactivity of these molecules are still to be elucidated, including their mode of binding to certain metal cations or materials surfaces. In this context, we have developed novel, efficient, user-friendly, and cost-effective synthetic protocols based on ball-milling, for the 17O and 18O isotopic labeling of two key fatty acids which are widely used in (nano)­materials science, namely stearic and oleic acid. Labeled molecules were analyzed by 1H and 13C solution NMR, IR spectroscopy, and mass spectrometry (ESI-TOF and LC-MS), as well as 17O solid state NMR (for the 17O labeled species). In both cases, the labeling procedures were scaled-up to produce up to gram quantities of 17O- or 18O-enriched molecules in just half-a-day, with very good synthetic yields (all ≥84%) and enrichment levels (up to an average of 46% per carboxylic oxygen). The 17O-labeled oleic acid was then used for the synthesis of a metal soap (Zn-oleate) and the surface-functionalization of ZnO nanoparticles (NPs), which were characterized for the first time by high-resolution 17O NMR (at 14.1 and 35.2 T). This allowed very detailed insight into (i) the coordination mode of the oleate ligand in Zn-oleate to be achieved (including information on Zn···O distances) and (ii) the mode of attachment of oleic-acid at the surface of ZnO (including novel information on its photoreactivity upon UV-irradiation). Overall, this work demonstrates the high interest of these fatty acid-enrichment protocols for understanding the structure and reactivity of a variety of functional (nano)­materials systems using high resolution analyses like 17O NMR.

Sustainability Assessment of Mechanochemistry by Using the Twelve Principles of Green Chemistry

“…[101] Notably, LAG has also enabled the establishment of practical and economic isotope labelling protocols. [102][103][104][105] But not only liquids have been used as auxiliaries in ball milling reactions, the addition of catalytic amounts of solid ionic salts has also been a common practice. [106] Additionally, silica, alumina, sodium chloride or sodium sulfate rank among the most often used solid additives in ball milling reactions.…”

“…Moreover, in situ released liquid products in mechanochemical transformations have been observed to accelerate chemical reactions, [100] thus indicating the possibility for LAG catalysis (Figure 4c) [101] . Notably, LAG has also enabled the establishment of practical and economic isotope labelling protocols [102–105] …”

Cost-efficient and user-friendly 17O/18O labeling procedures of fatty acids using mechanochemistry

“…[7][8][9] Lastly, regarding 17 O labeling, it is only very recently that we demonstrated that the 17 O enrichment of free FAs could be of great interest for (nano)materials science applications, by providing unique insight into the structure of metal soaps and in the surface reactivity of functionalized nano-particles. 10 Despite the great potential that 17 O/ 18 O-labeled FAs could offer to the research community, their use remains scarce compared to 2 H and 13 C labeled species. One of the reasons to this comes from the limited access to 17 O/ 18 O-labeled FAs, which are not commercially available and require to be synthesized.…”

“…In order to address the need for efficient and scalable 17 O/ 18 O labeling protocols which would be generally applicable to a broad range of FA substrates, we have developed alternative synthetic approaches using mechanochemistry, 12 where the 17 O/ 18 O enrichment is performed at ambient temperature and pressure using only few mL of H 2 O*. 13 Recently, we adapted this methodology for the first time for the synthesis of 17 O and 18 O-labeled oleic and stearic acids, and also scaled-up producing up to 1 g of 17 O-labeled acids for less than 280 h. 10 In this paper, we first demonstrate how by adapting our previous strategy, the scope of 17 O/ 18 O-labeled free FAs can be extended to other saturated FAs with the chain-length varying between C12 to C18 and also to PUFAs containing up to four double bonds, and how detailed analyses of reaction media can help determine working conditions for future syntheses. Then, we demonstrate how an original and efficient labeling scheme based on saponification of the ester derivatives can be used for the 17 O/ 18 O-labeling of the longest and highly sensitive PUFAs with five and six double bonds (EPA and DHA), thereby expanding the scope of approaches for enriching FAs.…”

“…), followed by hydrolysis of the activated acyl-imidazole intermediate using labeled water (2-3 equiv.). 10 For each substrate, the oxygen isotope enrichment protocol was first optimized using H 2…”