Progress 09/01/11 to 04/30/13
Outputs
OUTPUTS: For agrochemicals that are chiral, usually one enantiomer (either the right or left-handed version) is the active/desired pesticide or herbicide, while the other half causes side effects, different effects, similar effects or in limited cases, no effects. The inactive/undesired enantiomer is, and should be treated as, an impurity. This impurity not only limits the effectiveness of the agrochemical, but also leads to an increase in unjustifiable environmental pollutants. Thus, the resolution of optical isomers is of great importance in the development of safer, greener, and more effective agrochemicals. High performance liquid chromatography (HPLC) is the dominate tool for the separation of such enantiomers. This Small Business Innovation Research (SBIR) project supported the development of a new cyclic oligosaccharide cyclofructan for its use as a novel chiral selector for the enantiomeric separation of chiral agrochemicals. During the SBIR project, we have developed methods to enhance the purity of cyclofructans and develop the technology to use them as broadly effective chiral stationary phases. Specifically various types of derivatives such as; aliphatic, aromatic, basic, and neutral derivatives of the cyclofructan has been studied. Their degree of substitution and the best chromatographic support for these chiral selectors were examined. Altogether, 54 chiral agrochemicals such as acaricides, rodenticides, fungicides, and herbicides containing various functionalities such as anilides, diphenyl ethers, triazoles, imidazoles, chloroacetanilides, phenoxy propionic acids, arylphenoxypropionic acids and imidazolinones were used as test analytes to determine the enantioselectivity of these new chiral stationary phases. Out of 54 analytes, 40 have shown enantioselectivity using these new cyclofructan based stationary phases. Normal phase mode followed by polar organic mode gave resulted in the best separation conditions. Overall neutral derivatives of cyclofructan such as 3,5-dimethylphenyl (DMP) carbamate derivative, isopropyl (IP) carbamate derivative and R-1-(1-naphthyl)ethyl (RN) carbamate derivative showed the best enantioselectivity towards the selected chiral agrochemicals. This technology can be directly used for the production of better, cleaner, and more effective agrochemicals products that have fewer negative environmental and biological impacts and can be applied in a manner in which the desired agricultural outcome is achieved more easily. Indeed this well help lead the industry to produce single enantiomer pesticides, herbicides and fertilizers that are more potent, hence requiring lower dosages. The results of this project fortify the importance of this unique class of chiral stationary phases based on cyclofructans. This unique enantioselective chromatographic media is likely to be the greatest advancement in the resolution of enantiomers in the past 15 years. These chiral selectors will play a major role as separation media in the production of enantiomerically pure or enriched agrochemicals, as well as, in the study of enantioselective phyto-biochemical processes. PARTICIPANTS: Nothing significant to report during this reporting period. TARGET AUDIENCES: Agrochemical sales is a vast world market which exceeded $119 billion in sales in 2009 and is expected to grown at a rate of 10.4% in the next 3 to 5 years. China and India are the world's largest users of agrochemicals. This has allowed Asia to dominate the market and account for 43% of sales. The US is the second largest revenue generator, bringing in approximately 20% of global agrochemical sales. Thus it is of great importance to continue to improve the technology used to develop novel US based agrochemicals in order to remain a competitive entity in this market. Furthermore, the production of novel herbicides and pesticides has lead to an increase in the number of chiral agrochemicals. Hence it is becoming more essential that the means to produce enantiomerically pure agrochemicals is improved and expanded. The most important tool that will be used in the development of single-enantiomer agrochemicals are chiral selectors or chiral stationary phases (CSP), which are employed during enantioselective separation processes (i.e. high performance liquid chromatography (HPLC), super-critical fluid chromatography (SFC), and preparative chromatography). Currently, there are no CSPs that can separate all chiral agrochemicals. For this reason, it is critical that novel CSPs are developed as to further aid in the production of more effective and safer novel pesticides and herbicides. We have found that specific synthetic modifications of cyclofructans greatly enhance its chiral selectivity for specific classes of molecules. For example, certain alkyl functionalized cyclofructans may be highly selective for chiral primary amines. Furthermore, we have found that highly substituted aryl functionalized cyclofructans lose their ability to discriminate between enantiomers of primary amines, but gain the ability to separate racemic acidic and neutral compounds. Also there is preliminary evidence that a single functionalized cyclofructan molecule can simultaneously associate with multiple analytes, thereby providing preparative capabilities. Clearly this is one of the most intriguing and unusual classes of molecules (which are relevant to the area of chiral molecular recognition) found in at least the last 15 years. In this Phase I SBIR we proposed refined the large-scale preparation of cyclofructan 6 (CF6) and cyclofructan 7 (CF7), developed the use of cyclofructans as CSPs in HPLC, and examined the enantiomeric selectivity of these CSPs towards chiral agrochemicals. This will be of great interest to agrochemical manufacturers and end users. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The crystal structure of cyclofructan 6 (CF6) reveals that six fructofuranose rings are arranged in spiral fashion around the crown ether skeleton, either up or down toward the mean plane of the crown ether. As a result, access to the 18-crown-6 core on that side of the macrocycle is blocked by the hydrogen bonded hydroxyl groups. We hypothesized that this inter-molecular H-bonding would cause native CF6 to have limited enantiomeric separation capabilities. For these reasons, it was evident that derivatization of cyclofructan was necessary to produce viable chiral selectors. It was observed that, when CF6 CSPs were made with either aliphatic or aromatic substituted-CF6s (with a low degree of hydroxyl group substitution), they exhibited tremendous enantioselectivity toward chiral primary amines. This suggests that the CF6 intramolecular hydrogen bonding is disrupted after partial derivatization, causing a "relaxation" of the molecular structure. This may expose the crown ether core and/ or other previously inaccessible hydrogen bonding sites of the CF6. The aliphatic-functionalized CF6 stationary phases separate primary amines most effectively, providing higher selectivity and/or higher efficiency. Although aliphatic-functionalized CF6 stationary phases with a low substitution degree were highly successful for the separations of primary amines, they show poor capabilities for separating most other analytes. The aromatic functionalized CF6 CSPs demonstrated complementary capability of enantiomeric selectivities, in that some analytes were baseline separated on one column, while only a partial separation or no separation was observed on other aromatic functionalized CF6 columns. From these results it was evident that the most effective derivatization of cyclofructans are IP-CF6 (isopropyl carbamate-CF6), DMP-CF7 (dimethylphenyl carbamate-CF7), and RN-CF6 (R-naphthylethyl carbamate-CF6). After the successful synthesis of neutral (aliphatic and aromatic) and basic chiral stationary phases based on cyclofructan, 54 chiral agrochemicals were screened on these columns. Altogether, 54 chiral agrochemicals such as acaricides, rodenticides, fungicides, and herbicides containing various functionalities such as anilides, diphenyl ethers, triazoles, imidazoles, chloroacetanilides, phenoxy propionic acids, arylphenoxypropionic acids and imidazolinones were used as test analytes to determine the enantioselectivity of these new chiral stationary phases. Out of 54 analytes, 40 have shown enantioselectivity using these new cyclofructan based stationary phases. Normal phase mode followed by polar organic mode gave resulted in the best separation conditions. Overall neutral derivatives of cyclofructan such as 3,5-dimethylphenyl (DMP) carbamate derivative, isopropyl (IP) carbamate derivative and R-1-(1-naphthyl)ethyl (RN) carbamate derivative showed the best enantioselectivity towards the selected chiral agrochemicals.
Publications
- No publications reported this period
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