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电子晶体学有望成为有机化学家的利器

发布时间:2018-11-28 访问次数:349次 来源:ACS美国化学会 分享:

Electron crystallography could be a powerful tool for organic chemistsby Bethany Halford


加州的化学家们成功地使用电子晶体学研究了多种有机化合物的微晶(晶格宽为2微米)。

Chemists in California were able to study microcrystals of multiple organic compounds using electron crystallography (grid holes are 2 μm across).

Credit: ChemRxiv

两个研究团队利用电子轰击技术展示了小分子的可视化


当化学家们想要确定分子的结构时,他们通常采用X射线晶体学。但化学家们经常无法生长出分析所需的大量高质量晶体。现在,一项针对较小晶体的、名为电子晶体学的相似技术有望成为可替代的选择。两个独立工作的研究团队表明,该方法可以快速确定有机小分子的结构,相比于X射线晶体学技术,它使有机化学家们能够分析更广范围的小分子。

电子晶体学和X射线晶体学很相似,但科学家们研究的是通过向晶体发射电子(而不是X射线)而生成的衍射图案。与X射线相比,电子与晶体中分子的相互作用更强烈,这意味着研究人员可以使用非常少量的材料——晶体可以小到100纳米。用X射线晶体学研究的晶体通常需要在所有维度上达到至少5微米。

科学家们尚没有经常地使用电子晶体学来研究有机分子,因为电子束往往在还未收集到足够的数据之前就破坏了晶体。但近年来,研究人员已设法改良了此技术,从而可用于研究易受破坏的生物分子,如蛋白质。他们将样品冷却至低温,并使用衰减的电子束。

两个研究团队发现他们可以采用类似的改良技术来分析微小的有机化合物晶体。瑞士保罗谢勒研究所  的科学家Tim Gruene率先在欧洲开展了一项研究(Angew.Chem.Int.Ed.2018,DOI:10.1002 / anie.201811318)。美国团队则由加州大学洛杉矶分校的Jose A. Rodriguez、Hosea M. Nelson和Tamir Gonen以及加州理工学院的Brian M. Stoltz领导(ChemRxiv2018,DOI:10.26434/ chemrxiv.7215332.v1,ACS Cent.Sci待出版)。

Gruene和Gonen都指出,使用改良的电子晶体学技术来研究有机分子并非创举。他俩之前都在晶体学和分子生物学期刊上发表过这些技术的结果。但这些报道很大程度上被化学界忽视了

在新的报道中,两个团队通过他们可以打开胶囊或研磨一种非处方药片(如止痛药对乙酰氨基酚)及使用该技术确定活性药物成分的结构来强调该技术对有机化学家的作用并。他们还将电子晶体学应用于较大的有机化合物(如,欧洲团队研究了亚甲蓝衍生物、美国团队研究了硫链丝菌素)。Nelson说,对一些粉末的粗略分析可以在短短20分钟内完成,类似于简单的X射线晶体学实验。

加州大学伯克利分校的有机化学家Tom Maimone说:“看到一种非处方的感冒和流感药物胶囊被打开,其中的异质粉末在原子级分辨率下得到分析,这非常棒,即使这种技术仅适用于一部分有机小分子,这些论文所显示的成果也令人惊叹。”

该技术确实有局限性。虽然分析仅需要少量材料,但该材料必须是结晶体。并且,目前该技术只能确定一个分子的相对立体化学,而不是它的绝对立体化学。

即便如此,研究人员还是认为这项技术将受到有机化学家和其他对小分子感兴趣的研究人员的欢迎,前提是他们可以获得所需的仪器。Nelson指出,加州大学洛杉矶分校只有一台用于电子晶体学的低温电子显微镜,主要由该校的生物学家们使用。 Gruene说,他的仪器实际上是一个原型,由一个精密的探测器连接到一台电子显微镜而组成。Nelson和Gruene都希望通过展示这项技术的作用,以吸引更多的仪器制造商设计出有机化学家所需要的电子显微镜。

When chemists want to determine the structure of a molecule, they typically turn to X-ray crystallography. But chemists often find they can’t grow the large, high-quality crystals required for analysis. Now, a similar technique, known as electron crystallography, which works with smaller crystals, is poised to become an alternative. Two teams working independently show the method quickly determines the structures of small organic compounds, offering organic chemists the ability to analyze a wider array of small molecules than they can with X-ray crystallography.

Electron crystallography is similar to X-ray crystallography, but scientists study the diffraction pattern made by firing electrons at a crystal rather than X-rays. Electrons interact more strongly with the molecules in crystals than X-rays do, which means researchers can use vanishingly small amounts of material—crystals as small as 100 nm. Crystals studied with X-ray crystallography typically need to be at least 5 µm in all dimensions.

Scientists haven’t used electron crystallography to study organic molecules regularly because the electron beam tends to destroy the crystals before enough data can be collected. But in recent years, researchers have managed to modify the technique so that it can be used to study delicate biomolecules, such as proteins. They cool samples down to cryogenic temperatures and use an attenuated electron beam.

Two teams found they could apply similar modifications to analyze tiny crystals of organic compounds. Tim Gruene, a scientist at the Paul Scherrer Institute, spearheaded a research effort based in Europe (Angew. Chem. Int. Ed. 2018, DOI: 10.1002/anie.201811318). A U.S.-based team was led by Jose A. Rodriguez, Hosea M. Nelson, and Tamir Gonen of the University of California, Los Angeles, along with California Institute of Technology’s Brian M. Stoltz (ChemRxiv2018, DOI: 10.26434/chemrxiv.7215332.v1, with publication pending in ACS Cent. Sci.).

Using modified electron crystallography techniques to study organic molecules isn’t new, both Gruene and Gonen point out. Both researchers have previously published results from such techniques in crystallography and molecular biology journals. But those reports went largely unnoticed by the chemistry community.

In the new reports, both teams highlight the technique for organic chemists by showing that they can crack open a capsule or grind up a tablet of over-the-counter medicine, such as the painkiller acetaminophen, and use the technique to determine the structure of the active pharmaceutical ingredient. They also apply electron crystallography to larger organic compounds, such as a methylene blue derivative, in the case of the European team, and the antibiotic thiostrepton, in the case of the U.S. team. A rough analysis of some powders could be done in as little as 20 minutes, Nelson says, which is similar to simple X-ray crystallography experiments.

“To see an over-the-counter cold and flu medicine capsule being cracked open and the heterogeneous powder inside analyzed at atomic-level resolution is awesome,” says Tom Maimone, an organic chemist at the University of California, Berkeley. “Even if this technique only works for a subset of organic small molecules, what is shown in these papers is stunning.”

The technique does have limitations. While the analysis requires only a small amount of material, that material must be crystalline. And at the moment, the technique can only determine a molecule’s relative stereochemistry, not its absolute stereochemistry.

Even so, the researchers expect this technique will be popular among organic chemists and other researchers interested in small molecules, provided they can gain access to the instruments they need. Nelson points out that UCLA has only one cryo-electron microscope for performing electron crystallography, and it’s mainly used by the school’s biologists. Gruene says his instrument is really a prototype, with a sophisticated detector connected to an electron microscope. Both Nelson and Gruene hope by showing what this technique can do, more instrument makers will design electron microscopes with organic chemists in mind.

This article is reproduced with permission from Chemical & Engineering News (© American Chemical Society). The article was first published on OCTOBER 23, 2018 | APPEARED IN VOLUME 96, ISSUE 43