Automated synthesis

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A fully automated radiosynthesis module Radiosynthesis module.jpg
A fully automated radiosynthesis module

Automated synthesis or automatic synthesis is a set of techniques that use robotic equipment to perform chemical synthesis in an automated way. [1] Automating processes allows for higher efficiency and product quality although automation technology can be cost-prohibitive and there are concerns regarding overdependence and job displacement. Chemical processes were automated throughout the 19th and 20th centuries, with major developments happening in the previous thirty years, as technology advanced. Tasks that are performed may include: synthesis in variety of different conditions, sample preparation, purification, and extractions. Applications of automated synthesis are found on research and industrial scales in a wide variety of fields including polymers, personal care, and radiosynthesis.

Contents

Process

Flow chart comparing the procedures of an automated synthesis versus a manual or traditional synthesis. Automated versus Manual Synthesis Comparison Chart.png
Flow chart comparing the procedures of an automated synthesis versus a manual or traditional synthesis.

An automated synthesis is very similar in procedure to performing a manual synthesis. The overseeing chemist decides on a target molecule then formulates the experimental plan, which is a sequential series of steps. Then, they collect the required equipment and execute the plan. The automated synthesis follows the same pathway, except that the computer devises and executes the experimental plan. However, human revision is usually still required to ensure the automated route is practical and there are no implicit steps or conditions missing from the proposed procedure. [2]

In organic synthesis, organic synthesis software is used to automate the process of identifying sequences of reactions or routes that can be used to synthesize organic compounds. [3]

Benefits of automated synthesis

Automation of synthesis has three main benefits: increased efficiency, quality (yields and purity), and safety, all resulting from decreased human involvement. [4] As machines work faster than humans and are not prone to human error, throughput and reproducibility increases. [5] Additionally, as humans spend less time in the lab exposure to dangerous chemicals is significantly decreased. [6] This allows chemists additional time for theory and collaborative discussions.

Additional benefits include: multitasking, performing tasks beyond the scope of human precision or ability, exhaustive analysis, etc.

Concerns with automated synthesis

The primary concern of automated synthesis is job displacement. [4] Other concerns are high initial investment and maintenance costs, privacy concerns, and an over-dependence on technology. [4] There are also ethical concerns, regarding the use of artificial intelligence and robotics. See Ethics of artificial intelligence, Robot ethics, Machine ethics.

Parts of procedures and techniques were automated throughout the 19th and 20th centuries, using simple circuit boards. The first fully automatic synthesis was a peptide synthesis by Robert Merrifield and John Stewart in 1966. [7] Applications of artificial intelligence to organic synthesis also started in the 1960s with the Dendral Project, which helped organic chemists characterize and identify molecules using mass spectrometry. [8] True computer-assisted organic synthesis software (CAOS) such as LHASA became feasible as artificial intelligence and machine learning developed in the 1980s. [3] Important developments in automated radiosynthetic modules were also made in the 1980s. [9]

In the late 1990s, the main challenge of automation was overcoming phase-separation issues and increasing system integration. [5] At this time there were only specific systems that belonged to one of four designs: a flow reactor, a batch reactor connected by flow lines, one robot, two robots: one for synthesis and one for analysis, and special larger systems that were a combination of the aforementioned. [5]

The 2000s and 2010s saw significant development in industrial automation of molecules [10] as well as the emergence of general synthesis systems that could synthesise a wide variety of molecules on-demand, whose operation Melanie Trobe and Martin D. Burke compared to that of a 3D printer. [11]

Applications

Automated synthesis systems find new applications with a development of new robotic platforms. Possible applications include: uncontrolled synthesis, time-dependent synthesis, radiosynthesis, synthesis in demanding conditions (low temperatures, presence of specific atmosphere like CO, H2, N2, high pressure or under vacuum) or whenever the same or similar workflow needs to be applied multiple times with the aim to: optimize reactions, synthesize many derivatives in small scale, perform reactions of iterative homologations or radiosynthesis.

Automated synthesis workflows are needed both in academic research and a wide array of industrial R&D settings (pharmaceuticals, agrochemicals, fine & specialty chemicals, renewables & energy research, catalysts, polymers, ceramics & abrasives, porous materials, nanomaterials, biomaterials, lubricants, paints & coatings, home care, personal care, nutrition, forensics).

Polymers

Parallel synthesis

Overall, automated synthesis has improved the efficiency for the parallel synthesis and combinatorial methods of polymers. These techniques aim to design new materials, in addition to studying the relationships of their structure and properties. [12] However, while screening for polymers enables this investigation, it becomes increasingly demanding for researchers to create the libraries for these synthetic compositions. [13] In addition, preparation requires a large number of repetitive reactions to be completed, leading to an immense burden of planning and labor. [14] Using automated synthesis, this process can be refined, increasing the efficiency of the reaction and removing the impact of human error. [14]

Polycondensation

Polycondensation involves the formation of polymers through condensation reactions between different species, creating condensation polymers. With automated synthesis, General electric manufactured an approach for melt-polymerizations of BPA and diphenyl carbonate (DPC), using sodium hydroxide (NaOH) as the catalyst. [15] Once the results were analyzed, it was shown that, by using an automated method of polymerization, the effect of varying the catalyst amount became more distinct and improved the reproducibility for the reaction. [15] Furthermore, it demonstrated an increase within the homogeneity of the polymers in the microreactors. [15]

Free-radical polymerization
Automated synthesis and post-polymerization functionalization process Automated synthesis and postpolymerization functionalization process.jpg
Automated synthesis and post-polymerization functionalization process

In addition to polycondensation, automated synthesis has been applied to the various methods of radical polymerization, such as ring-opening and polyolefins. This includes free-radical polymerization, such as the development of an automated process to synthesize and evaluate molecularly imprinted polymers (MIPs). [12] Through thermal initiation, around sixty polymers could be prepared in parallel and evaluated through their binding constants to the imprinted analytes. [12] Furthermore, adding another approach to the repertoire, Long et al. demonstrated the abilities of robotic systems and their use with varying the monomer for the synthesis of poly(styrene-co-methyl methacrylate) and poly(styrene-co-butyl methacrylate). [12] After automatically precipitating, the products were characterized with standard analytics and added to the polymer library. [12] Another example includes the method described by Symyx Technologies Inc. with the application of an ink-jet printer, delivering different ratios of styrene and acrylonitrile, which was used as the terminator. [12]

While these are examples of suspension polymerization, the first instance of automated synthesis for parallel emulsion was reported by Voorn et al. with five parallel reactors containing well-defined systems of styrene and vinyl acetate. [16] After optimizing the vortex speed, the results between the methods of automated synthesis and classical stirring for emulsion polymerization were compared, which found that the products were comparable. [16]

Controlled radical polymerization

While juxtaposed against free-radical polymerization, the application of automated synthesis can be utilized for controlled radical polymerization too. These methods have been used within reversible addition-fragmentation transfer (RAFT), atom-transfer radical (ATRP), and nitroxide-mediated polymerizations, demonstrating the ability of robots to improve efficiency and reduce the hardship of performing reactions. [12] For example, with the automatic dispensation of reagents, Symyx Technologies Inc. was able to polymerize styrene and butyl acrylate through ATRP. [12] In addition, this functionality was supported by Zhang et al. within their research, finding that reproducibility and comparability were equivalent to classical ATRP. [17]

Ring-opening polymerization

With ring-opening polymerization, automated synthesis has been used for rapid screening and optimization, including with catalyst + initiator systems and their polymerization conditions. For example, Hoogenboom et al. determined the optimal temperature for the polymerization of 2-ethyl-2-oxazoline in dimethylacetamide (DMAc), allowing for individual heating of the parallel reactors, which shortened the time needed for preparation and analysis. [18]

Polyolefins

To aid with the catalyst research for polyolefins, Symyx Technologies Inc. used automated synthesis to create a library of palladium and nickel catalysts, which were screened for ethylene polymerization. [12] This process found that the largest polyethylene polymers were created by the complexes with the highest steric hindrance for the ortho-positions of the aryl rings, while electronic factors did not influence yield or molecular weight. [12] In addition, Tuchbreiter and Mülhaupt used automated synthesis to demonstrate the improvements of minireactors for the polymerization of olefins, with quality improving as compared to utilizing simple arrays. [19]

Supramolecular polymerization

Within the field of supramolecular polymerization, Schmatloch et al. used automated synthesis to create main-chain supramolecular coordination polymers, reacting bis(2,2′:6′,2″-terpyridine)-functionalized poly(ethylene oxide) with various metal(II) acetates. [12] From this, it was revealed that classical laboratory approaches could be transferred to automatic synthesis, optimizing the processes to increase efficiency and aid with reproducibility. [12]

Recent developments

Schematic of automated process for PET-RAFT and Enz-RAFT. Schematic of automated process for PET-RAFT and Enz-RAFT.jpg
Schematic of automated process for PET–RAFT and Enz-RAFT.

Over the years, multiple synthesizers have been developed to assist with automated synthesis, including the Chemspeed Accelerator (SLT106, SLT II, ASW2000, SwingSLT, Autoplant A100, and SLT100), the Symyx system, and Freeslate ScPPR. [13] Recently, researchers have investigated the optimization of these methods for controlled/living radical polymerization (CLRP), which faces issues with oxygen intolerance. [13] This research has led to the development of oxygen-tolerant CLRP, including with the use of enzyme degassing of RAFT (Enz-RAFT), atom-transfer radical (ATRP) that possesses tolerance to air, and photoinduced electron/energy transfer–RAFT (PET–RAFT) polymerization. [13] Through the use of liquid-handling robots, Tamasi et al. demonstrated the use of automated synthesis with executing multi-step procedures, enabling the reactions to investigate more elaborate schemes, such as with scale and complexity. [13]

Robotic platforms

Automated synthesis systems are laboratory robots that combine of software and hardware. [21] As synthesis is a linear combination of steps, the individual steps can be modularized into hardware that accomplishes the specific step (mixing, heating or cooling, product analysis, etc.). Such hardware includes robotic arms that use dispensers and grippers to transfer materials and shakers that adjust the stirring speed and cartesian coordinate system robots that operate on a X Y Z axis and can move items and perform synthesis within designated bounds. [22]

Conditions of reactions (atmosphere, temperature, pressure) are controlled with the help of peripherals like: gas cylinders, vacuum pump, reflux system and cryostat. Modular platforms use a variety of tools in order to perform all operations needed in synthesis. There are many commercial modular hardware solutions available to execute synthesis. New software programs are available that can compile an automated synthesis procedure in executable code directly from existing literature. [23] There are also software programs that can retro-synthetically generate a procedure at the level of proficiency of a graduate student. [2]

Related Research Articles

<span class="mw-page-title-main">Symyx Technologies</span>

Symyx Technologies, Inc. was a company that specialized in informatics and automation products. Symyx provided software solutions for scientific research, including Enterprise Laboratory Notebooks and products for combinatorial chemistry. The software part of the business became part of Accelrys, Inc. in 2010 and then in 2014 this company merged with Dassault Systèmes. Symyx also offered laboratory robotics systems for performing automated chemical research, which in 2010 was spun out as Freeslate, Inc.

In polymer chemistry, living polymerization is a form of chain growth polymerization where the ability of a growing polymer chain to terminate has been removed. This can be accomplished in a variety of ways. Chain termination and chain transfer reactions are absent and the rate of chain initiation is also much larger than the rate of chain propagation. The result is that the polymer chains grow at a more constant rate than seen in traditional chain polymerization and their lengths remain very similar. Living polymerization is a popular method for synthesizing block copolymers since the polymer can be synthesized in stages, each stage containing a different monomer. Additional advantages are predetermined molar mass and control over end-groups.

<span class="mw-page-title-main">Copolymer</span> Polymer derived from more than one species of monomer

In polymer chemistry, a copolymer is a polymer derived from more than one species of monomer. The polymerization of monomers into copolymers is called copolymerization. Copolymers obtained from the copolymerization of two monomer species are sometimes called bipolymers. Those obtained from three and four monomers are called terpolymers and quaterpolymers, respectively. Copolymers can be characterized by a variety of techniques such as NMR spectroscopy and size-exclusion chromatography to determine the molecular size, weight, properties, and composition of the material.

<span class="mw-page-title-main">Laboratory robotics</span> Using robots in biology or chemistry labs

Laboratory robotics is the act of using robots in biology, chemistry or engineering labs. For example, pharmaceutical companies employ robots to move biological or chemical samples around to synthesize novel chemical entities or to test pharmaceutical value of existing chemical matter. Advanced laboratory robotics can be used to completely automate the process of science, as in the Robot Scientist project.

In chemistry, radical initiators are substances that can produce radical species under mild conditions and promote radical reactions. These substances generally possess weak bonds—bonds that have small bond dissociation energies. Radical initiators are utilized in industrial processes such as polymer synthesis. Typical examples are molecules with a nitrogen-halogen bond, azo compounds, and organic and inorganic peroxides.

<span class="mw-page-title-main">Radical polymerization</span> Polymerization process involving free radicals as repeating units

In polymer chemistry, free-radical polymerization (FRP) is a method of polymerization by which a polymer forms by the successive addition of free-radical building blocks. Free radicals can be formed by a number of different mechanisms, usually involving separate initiator molecules. Following its generation, the initiating free radical adds (nonradical) monomer units, thereby growing the polymer chain.

<span class="mw-page-title-main">Polystyrene sulfonate</span> Drug class

Polystyrene sulfonates are a group of medications used to treat high blood potassium. Effects generally take hours to days. They are also used to remove potassium, calcium, and sodium from solutions in technical applications.

<span class="mw-page-title-main">Reversible addition−fragmentation chain-transfer polymerization</span> Chemical reaction that produces polymers

Reversible addition−fragmentation chain-transfer or RAFT polymerization is one of several kinds of reversible-deactivation radical polymerization. It makes use of a chain-transfer agent (CTA) in the form of a thiocarbonylthio compound to afford control over the generated molecular weight and polydispersity during a free-radical polymerization. Discovered at the Commonwealth Scientific and Industrial Research Organisation (CSIRO) of Australia in 1998, RAFT polymerization is one of several living or controlled radical polymerization techniques, others being atom transfer radical polymerization (ATRP) and nitroxide-mediated polymerization (NMP), etc. RAFT polymerization uses thiocarbonylthio compounds, such as dithioesters, thiocarbamates, and xanthates, to mediate the polymerization via a reversible chain-transfer process. As with other controlled radical polymerization techniques, RAFT polymerizations can be performed under conditions that favor low dispersity and a pre-chosen molecular weight. RAFT polymerization can be used to design polymers of complex architectures, such as linear block copolymers, comb-like, star, brush polymers, dendrimers and cross-linked networks.

<span class="mw-page-title-main">Horseradish peroxidase</span> Chemical compound and enzyme

The enzyme horseradish peroxidase (HRP), found in the roots of horseradish, is used extensively in biochemistry applications. It is a metalloenzyme with many isoforms, of which the most studied type is C. It catalyzes the oxidation of various organic substrates by hydrogen peroxide.

<span class="mw-page-title-main">Oxazoline</span> Chemical compound

Oxazoline is a five-membered heterocyclic organic compound with the formula C3H5NO. It is the parent of a family of compounds called oxazolines, which contain non-hydrogenic substituents on carbon and/or nitrogen. Oxazolines are the unsaturated analogues of oxazolidines, and they are isomeric with isoxazolines, where the N and O are directly bonded. Two isomers of oxazoline are known, depending on the location of the double bond.

<span class="mw-page-title-main">Thiol-yne reaction</span> Chemical addition of an –SH and –C≡CH molecule

In organic chemistry, the thiol-yne reaction is an organic reaction between a thiol and an alkyne. The reaction product is an alkenyl sulfide.

<span class="mw-page-title-main">Living free-radical polymerization</span>

Living free radical polymerization is a type of living polymerization where the active polymer chain end is a free radical. Several methods exist. IUPAC recommends to use the term "reversible-deactivation radical polymerization" instead of "living free radical polymerization", though the two terms are not synonymous.

<span class="mw-page-title-main">Reversible-deactivation radical polymerization</span> Type of chain polymerization

In polymer chemistry, reversible-deactivation radical polymerizations (RDRPs) are members of the class of reversible-deactivation polymerizations which exhibit much of the character of living polymerizations, but cannot be categorized as such as they are not without chain transfer or chain termination reactions. Several different names have been used in literature, which are:

<span class="mw-page-title-main">Sequence-controlled polymer</span> Macromolecule involving monomeric sequence-control

A sequence-controlled polymer is a macromolecule, in which the sequence of monomers is controlled to some degree. This control can be absolute but not necessarily. In other words, a sequence-controlled polymer can be uniform or non-uniform (Ð>1). For example, an alternating copolymer synthesized by radical polymerization is a sequence-controlled polymer, even if it is also a non-uniform polymer, in which chains have different chain-lengths and slightly different compositions. A biopolymer with a perfectly-defined primary structure is also a sequence-controlled polymer. However, in the case of uniform macromolecules, the term sequence-defined polymer can also be used.

<span class="mw-page-title-main">Graft polymer</span> Polymer with a backbone of one composite and random branches of another composite

In polymer chemistry, graft polymers are segmented copolymers with a linear backbone of one composite and randomly distributed branches of another composite. The picture labeled "graft polymer" shows how grafted chains of species B are covalently bonded to polymer species A. Although the side chains are structurally distinct from the main chain, the individual grafted chains may be homopolymers or copolymers. Graft polymers have been synthesized for many decades and are especially used as impact resistant materials, thermoplastic elastomers, compatibilizers, or emulsifiers for the preparation of stable blends or alloys. One of the better-known examples of a graft polymer is a component used in high impact polystyrene, consisting of a polystyrene backbone with polybutadiene grafted chains.

<span class="mw-page-title-main">Knotted polymers</span>

Single Chain Cyclized/Knotted Polymers are a new class of polymer architecture with a general structure consisting of multiple intramolecular cyclization units within a single polymer chain. Such a structure was synthesized via the controlled polymerization of multivinyl monomers, which was first reported in Dr. Wenxin Wang's research lab. These multiple intramolecular cyclized/knotted units mimic the characteristics of complex knots found in proteins and DNA which provide some elasticity to these structures. Of note, 85% of elasticity in natural rubber is due to knot-like structures within its molecular chain.
An intramolecular cyclization reaction is where the growing polymer chain reacts with a vinyl functional group on its own chain, rather than with another growing chain in the reaction system. In this way the growing polymer chain covalently links to itself in a fashion similar to that of a knot in a piece of string. As such, single chain cyclized/knotted polymers consist of many of these links, as opposed to other polymer architectures including branched and crosslinked polymers that are formed by two or more polymer chains in combination.

Copper-based reversible-deactivation radical polymerization is a member of the class of reversible-deactivation radical polymerization. In this system, various copper species are employed as the transition-metal catalyst for reversible activation/deactivation of the propagating chains responsible for uniform polymer chain growth.

<span class="mw-page-title-main">1,1-Diphenylethylene</span> Chemical compound

1,1-Diphenylethylene is an aromatic hydrocarbon with chemical formula C14H12.

<span class="mw-page-title-main">Hydroxyethyl acrylate</span> Organic chemical-monomer

Hydroxyethyl acrylate is an organic chemical and an aliphatic compound. It has the formula C5H8O3 and the CAS Registry Number 818–61–1. It is REACH registered with an EU number of 212–454–9. It has dual functionality containing a polymerizable acrylic group and a terminal hydroxy group. It is used to make emulsion polymers along with other monomers and the resultant resins are used in coatings, sealants, adhesives and elastomers and other applications.

<span class="mw-page-title-main">Yves Gnanou</span> French chemist, academic and author

Yves Gnanou is a French chemist, academic and author. He is the Ibn Alhaytham Distinguished Professor of Chemistry at King Abdullah University of Science and Technology.

References

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  13. 1 2 3 4 5 6 Tamasi, Matthew; Kosuri, Shashank; DiStefano, Jason; Chapman, Robert; Gormley, Adam J. (February 2020). "Automation of Controlled/Living Radical Polymerization". Advanced Intelligent Systems. 2 (2): 1900126. doi:10.1002/aisy.201900126. PMC   9113399 . PMID   35586369.
  14. 1 2 Rojas, Ramiro; Harris, Nicole K.; Piotrowska, Karolina; Kohn, Joachim (January 2009). "Evaluation of automated synthesis for chain and step-growth polymerizations: Can robots replace the chemists?". Journal of Polymer Science Part A: Polymer Chemistry. 47 (1): 49–58. Bibcode:2009JPoSA..47...49R. doi:10.1002/pola.23119.
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  19. ↑ Tuchbreiter, Arno; Mülhaupt, Rolf (13 September 2001). "The polyolefin challenges: catalyst and process design, tailor-made materials, high-throughput development and data mining". Macromolecular Symposia. 173 (1): 1–20. doi:10.1002/1521-3900(200108)173:1<1::AID-MASY1>3.0.CO;2-T.
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