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<\/div>\n<\/div>A machine for synthesizing small molecules at the University of Illinois at Urbana\u2013Champaign relies on syringe pumps to push reagents into reaction stations.<\/span>Credit: L. Brian Stauffer, Univ. Illinois<\/p>\n<\/figcaption><\/figure>\n <\/p>\n <\/p>\n In a laboratory at the University of Liverpool, UK, a chemist painstakingly mixes, measures, weighs and analyses, trying to find new materials that might be used to make hydrogen from water and light. But this chemist is not your average scientist. It is a robot.<\/p>\n The robot is just one example of numerous efforts to automate the time-consuming process of making molecules. Back in 1972, the synthesis of vitamin B12 took 91 postdocs and a dozen PhD students 12 years to complete. Almost five decades later, some syntheses remain nearly as complex.<\/p>\n But a growing group of researchers hopes to reduce some of that complexity to push-button simplicity, using automation to accelerate the field, just as has been achieved for molecular biology.<\/p>\n \u201cAutomated synthesis of DNA and biological polymers enabled molecular biology,\u201d says Peter Seeberger, director of the Max Planck Institute of Colloids and Interfaces in Potsdam, Germany. \u201cIt\u2019s so well established, most people don\u2019t think about it any more.\u201d<\/p>\n But automating the synthesis of all possible compounds is entirely different. The number of ways to combine atoms into molecules is astronomical, and the technology to build any arbitrary molecule doesn\u2019t yet exist. But researchers are making slow, steady progress by focusing on certain compounds, such as small molecules that are potential drug candidates.<\/p>\n The resulting systems could shake up synthetic chemistry by automating not only the repetitive legwork, but also decision-making and recipe development. The technical challenges are substantial, says chemist Martin Burke at the University of Illinois at Urbana\u2013Champaign, but the time is right. He compares the state of the field to the early stages of the Human Genome Project. At the time, he says, the technology to do the sequencing work didn\u2019t exist, but researchers pushed ahead anyway. \u201cPeople assumed that they were going to figure it out.\u201d The same, Burke argues, is true of chemistry today. \u201cChemistry now has its opportunity for its Moon mission. This is it.\u201d<\/p>\n <\/p>\n \u2018Chemputer\u2019 upgrade<\/strong><\/p>\n One argument in favour of automation is that chemical synthesis is tedious and difficult, even for experts. For many researchers, the process is as much art as science. Burke says that chemistry has become \u201can artistic expression of oneself through our molecule making\u201d. Mimi Hii, director of Imperial College London\u2019s Centre for Rapid Online Analysis of Reactions, argues that this is a bad thing. \u201cChemistry is a science, it shouldn\u2019t be an art.\u201d<\/p>\n The US Defense Advanced Research Projects Agency (DARPA) in Arlington, Virginia, has set up a programme called Make-It to develop a machine to help remove those barriers.<\/p>\n Make-It is pursuing both hardware and software solutions for automation, says programme manager Anne Fischer. One approach the programme supports is a robotic arm, developed at the Massachusetts Institute of Technology in Cambridge, which uses preloaded cartridges to automate synthetic steps such as heating, mixing and separating chemicals.<\/p>\n Lee Cronin\u2019s \u2018Chemputer\u2019 exemplifies a second approach. Cronin, a DARPA-funded chemist at the University of Glasgow, UK, describes Chemputer as a modular desktop-sized robotic synthesizer, which \u2018compiles\u2019 text-based recipes into instructions to drive laboratory automation hardware.<\/p>\n A robot chemist at the University of Liverpool, UK, sifts through thousands of materials to find a photocatalyst.<\/span>Credit: Univ. Liverpool<\/p>\n<\/figcaption><\/figure>\n Cronin has eight Chemputers in his lab, each costing \u00a325,000\u201330,000 (US$33,000\u201339,500), including all the associated chemistry kit, such as stirrers, evaporators and hotplates. His team has so far used those instruments to assemble six compounds, including a generic form of Pfizer\u2019s Viagra (sildenafil). Synthetic schemes are in development for 20 other compounds. \u201cTo make sildenafil takes 30 hours of lab time,\u201d Cronin says. But it takes under an hour to program Chemputer to do the same thing, so researchers are freed to spend more time on other tasks.<\/p>\n \u201cNo reactions that are out of reach for the human are out of reach for the Chemputer, in principle,\u201d Cronin says, although new modules would be needed to expand the number of possible molecules the instrument can create \u2014 that is, its \u2018chemical space\u2019. His team has set up an online platform, Chemify, from which interested chemists can download Chemputer assembly instructions.<\/p>\n <\/p>\n Back to the future<\/strong><\/p>\n A team led by Jeffrey Bode, an organic chemist at the Swiss Federal Institute of Technology (ETH) in Zurich, Switzerland, and Benedikt Wanner, co-founder of Synple Chem, an ETH Zurich start-up company, described a similar concept on the ChemRxiv preprint server at the end of March \u2014 a \u2018console\u2019-like computer with preloaded chemical applications that the team used to drive several classes of organic reaction commonly applied in drug discovery (T. Jiang\u00a0et al<\/i>. Preprint at ChemRxiv http:\/\/doi.org\/c4nd; 2019<\/a>).<\/p>\n Often, researchers start off small, and limit their chemistry to a simple set of starting materials. In 2015, for instance, Burke showcased an automated building-block approach using small organic molecules known as MIDA boronates (J. Li\u00a0et al. Science<\/i>\u00a0347<\/b>, 1221\u20131226; 2015<\/a>).<\/p>\n <\/p>\n![\"A](\"\/\/media.nature.com\/w800\/magazine-assets\/d41586-019-01246-y\/d41586-019-01246-y_16656252.gif\")
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