Greener Alternatives in Organic Synthesis Involving Carbonyl Groups: Dethioacetalization and Iron-Catalyzed Transfer Hydrogenation

By Diya Zhu, Member-at-Large for the GCI

A carbonyl functionality is a functional group composed of a carbon atom double-bonded to an oxygen atom (C=O). It is ubiquitous in nature as well as widely employed and studied in all areas of chemistry. In this blog, we will explore two common synthetic processes involving carbonyl groups with greener alternative reagents.

Dethioacetalization with NH4I

Carbonyl-containing compounds are abundant in nature, expressing a wide range of functionality. As targeted in many natural and non-natural product syntheses, the protection and deprotection of the carbonyl functional groups are critical and often require multiple steps. Common carbonyl protecting groups are dithianes and dithiolanes due to their easy accessibility and high stability under acidic/basic conditions. The traditional dethioacetalization is generally performed utilizing heavy-metal salts such as mercury(II) chloride, silver(II) nitrite, ceric ammonium nitrate, and selenium dioxide, of which the resulting waste is very toxic to the environment.1

From 1989 to 2005, serval hypervalent iodine compounds such as bis(trifluoroacetoxy)-iodobenzene (BTI), Dess-Martin periodinane (DMP), and o-iodoxybenzoic acid (IBX) have been employed as dethioacetalization reagents due to their low toxicity, high selectivity, and metal-ion free nature. While these reagents have a smaller environmental impact, they are still required in excess amount, which is economically wasteful.2, 3

Finally, in 2011, Ganguly and Mondal reported a mild, efficient, and greener dethioacetalization protocol using a catalytic amount of ammonium iodide with hydrogen peroxide.3 In this work, the deprotection was carried out with 10 mol% of nontoxic ammonium iodide and 30% hydrogen peroxide as the terminal oxidizer in an aqueous medium in the presence of sodium dodecylsulfate (SDS). This protocol (Figure 1) shows a high yield (>90%) deprotection of 1,3–dithianes and dithiolanes of activated aromatics and even deactivated and sterically encumbered substrates. The high tolerance, low environmental impact, mildness, operational simplicity, high throughput, and generality of the protocol make it an intriguing alternative.

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The greener dethioacetalization protocol by Ganguly and Mondal. [3]

Iron-catalyzed transfer hydrogenation with formic acid

Various catalyst systems for the reduction of carbonyl compounds have been established, such as Meerwein–Ponndorf–Verley (MPV) reduction.4 However, only a handful of protocols were reported for the transfer hydrogenation of aldehydes due to the difficulty in controlling the chemoselectivity in the process.

In these conversional protocols of transfer hydrogenation, many side-reactions (for example, aldol condensations) take place after deprotection by the base. The heavy-metal catalysts (such as rhodium, iridium, and ruthenium complexes) are expensive and often poisoned by the substrates, resulting in non-recyclable catalysts and many side-products. In addition, the hydrogenation of carbon-carbon double bonds (C=C) and aldehydes compete, resulting in poor chemoselectivity.5,6 Due to these drawbacks, there was a significant desire for more efficient and environmentally benign catalytic systems.

In the last decade, iron catalysts have received much attention due to their nontoxic, abundant, and inexpensive qualities. In 2013, Beller and his colleagues published an efficient iron-based catalyst system for the highly selective transfer hydrogenation of aldehydes under mild conditions.6 In this system, they suggested that iron-tetraphos complexes [(Fe(BF4)•6H2O and P(CH2CH2PPh2)3) are able to catalyze a wide range of substrates such as aromatic, aliphatic, and α,β-unsaturated aldehydes to the corresponding alcohols in excellent yields (>99%). Without the presence of a base, formic acid is used as a cheap, environmental friendly, and easy to handle hydrogen source. In addition, no significant amounts of side products were observed.

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The iron-catalyzed transfer hydrogenation with formic acid. [6]

In addition to these two examples, many chemical companies promote the idea of green chemistry and offer more green choices to reduce environmental impact without compromising the quality and efficacy of research.7

 

References:

  1. J. Corey, B. W. Erickson, Journal of Organic Chemistry 36 (1971), 3553; E. Vedejs, P. L. Fuches, Journal of Organic Chemistry 36 (1971), 366.
  2. S. Kirshnaveni, K. Surendra, Y. V. D. Nageswar, K. R. Rao, Synthesis 15 (2003), 2295. DOI: 10.1055/s-2003-41055
  3. C. Ganguly, P. Mondal, Synthetic Communications 41 (2011), 2374. DOI: 10.1080/00397911.2010.502995
  4. Gladiali, E. Alberico, Chemistry Society Reviews 35 (2006) 226. DOI: 10.1039/B513396C
  5. S. M. Samec, J.-E. Bäckvall, P. G. Andersson, P. Brandt, Chemistry Society Reviews 35 (2006), 237. DOI: 10.1039/b515269k
  6. Wienhöfer, F. A. Westerhaus, K. Junge, M. Beller, Journal of Organometallic Chemistry 744 (2013) 156. DOI: 10.1016/j.jorganchem.2013.06.010
  7. Sigma Aldrich Alternative Product Page. http://www.sigmaaldrich.com/chemistry/chemistry-products.html?TablePage=119262253 (accessed Oct 15, 2017).
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All Wrapped Up – Catalyst-Containing Wax Capsules Instead of Glove Boxes

All Wrapped Up – Catalyst-Containing Wax Capsules Instead of Glove Boxes

By Kevin Szkop, Symposium Coordinator for the GCI

What if you could do air-sensitive chemistry without a glove box or Schlenk line?

This is the idea behind the company XiMo, launched by Amir Hoveyda from Boston College, Richard Schrock from MIT and their co-workers.

Schrock, Hoveyda and many others work in the area of making carbon-carbon bonds.  The carbon-carbon bond is ubiquitous in nature, found in (nearly) every organic and naturally occurring molecule. The complexity of design that can be obtained from a seemingly simple chemical bond is unparalleled. The formation of carbon-carbon bonds is very important in the manufacturing of pharmaceuticals, food and natural products, agricultural chemicals, materials, and more. Notably, synthetic organic and inorganic chemists work together to design catalysts that are able to carry out this priceless transformation.

There have been many advances in this regard, especially in the field of coupling reactions and bond metathesis (the swapping of partners by a re-distribution of alkene and alkyne groups), both endeavours earning their discoverers Nobel prizes.1,2 However, a shortcoming in this field is the air- and moisture-sensitivity of the catalysts that need to be used for these transformations. The typical way of overcoming this problem is through the use of a glove box.

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Typical glove box used to protect air- and moisture-sensitive materials.

A glove box is an essential piece of laboratory equipment to the synthetic chemist. By providing an air- and moisture-free environment, sensitive chemistry can easily be performed.
While useful, glove boxes are expensive to buy and operate, require a lot of inert gas (argon or nitrogen) to maintain a clean and dry working atmosphere, and a lot of upkeep is needed to maintain their successful operation.

 

In efforts to address these issues, Amir Hoyveda from Boston College, Richard Schrock from MIT, and coworkers have launched the company XiMo3, which manufactures paraffin tablets containing air and moisture sensitive materials. Using less rigorous techniques for the exclusion of air and moisture from the reaction vessel than a glove box, the organic chemist can simply add the tablet to the desired reaction. The tablets will release their contents in the reaction solvent under mild heating conditions. Therefore, even though precautions must be taken, the overall process eliminates the need for a glove box.4

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Paraffin wax tablet

Many different factors affect the integrity of the paraffin wax tablets. The active compound must be able to dissolve in the reaction medium and release its contents under desirable conditions, it must be air- and water-stable, and the active compounds must be homogeneously dispersed within the volume of the tablet, but not on the surface. These problems have all been overcome since the company’s founding in 2005.

Some of the commercially available catalysts (shown below) are widely used in metathesis reactions for the construction of complex molecular carbon backbones.5,6,7 These reagents have been successfully incorporated into a paraffin tablet and show equivalent activity in selected reactions compared to the traditional catalyst in reactions performed under air- and moisture-free conditions.

 

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Typical metathesis catalysts embedded in paraffin wax tablets.

The company’s founders hope that this new technology will speed up research and development endeavours, particularly in the field of drug synthesis. Bypassing the need for a glovebox, the paraffin tablets will allow a wide range of organic chemists to explore the rich chemistry obtainable by these air sensitive catalysts.

 

References

  1. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2005/
  2. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2010/
  3. XiMo Technologies: http://www.ximo-inc.com/technology-updates
  4. Chemistry World News, Oct. 2016: https://www.chemistryworld.com/news/wax-pills-for-safe-and-simple-olefin-metathesis-hit-the-market/1017567.article
  5. Koh, M.-J.; Nguyen, T. T.; Zhang, H.; Schrock, R. R.; Hoveyda, A. H.Nature2016, 531,
  6. Lam, C. Zhu, K. V. Bukhryakov, P. Müller, A. H. Hoveyda, R. R. SchrockJ. Am. Chem. Soc. 2016, 138, 15774.
  7. T. Nguyen, M. J. Koh, X. Shen, F. Romiti, R. R. Schrock, A. H. HoveydaScience, 2016, 352, 569.

 

Challenges in Designing Non-Toxic Molecules: Using medicinal chemistry frameworks to help design non-toxic commercial chemicals

By Shira Joudan, Education Committee Coordinator for the GCI

Throughout the past 20 years, there have been numerous reports on the state of the science of designing non-toxic molecules, including three in this year alone.1–3 The idea of safe chemicals has been around for much longer than the green chemistry movement, however it is an important pillar in what it means for a chemical to be green. In fact, many scientists agree that the synthesis of safer chemicals is likely the least developed area of Green Chemistry, with lots of room for improvement.2 For more information, see our post and video on Green Chemistry Principle #4.

One expert on designing non-toxic molecules is Stephen C. DeVishira-blog-picto of the United States Environmental Protection Agency (US EPA). In a recent paper DeVito highlights some major challenges creating safer molecules, and discusses how we can approach this challenge.1 We require a societal change about how we think of toxicity, and this shift must begin with specific education.

How can we agree upon definition of a “safe” chemical?

We need to decide and agree upon parameters that deem a molecule safe, or non-toxic. Generally, most chemists agree that an ideal chemical will have no (or minimal) toxicity to humans or other species in the environment. It should also not bioaccumulate or biomagnify in food chains, meaning it should not build up in biota, or increase in concentration with increased trophic levels in a food chain. After its desired usage, an ideal chemical should break down to innocuous substances in the environment. Potency and efficacy are also important, as well as the “greenness” of its synthesis. Setting quantitative thresholds to these parameters and enforcing them is the largest challenge.

How do we tackle the over 90,000 current use chemicals?

Although not all of these chemicals are actually in use, they are all registered under the US EPA’s Toxic Substances Control Act (TCSA), which contains both toxic and non-toxic chemicals. Many chemicals that are being used should be replaced with safer alternatives, but there are so many that it seems terrifying to know where to begin. Another replacement option is designing new technologies that don’t require the function that these chemicals provide. About two-thirds of the chemicals registered in TCSA or Environment and Climate Change Canada’s Chemicals Management Plan were in use before registration was required. Unlike pharmaceuticals and pesticides which are heavily regulated by Health Canada, commercial chemicals do not require stringent toxicity tests. But things are changing in the US and in Canada. For example, Canada has just listed 1550 priority chemicals that will be addressed by 2020. When considering replacement for chemicals of concern, the most common barrier to reducing the use is currently “no known substitutes or alternative technologies”.

How do we ensure sufficient training on the concepts of safer chemical design?

Many people making new chemicals are unfamiliar with green chemistry and basic toxicology principles. Without the proper toolbox of knowledge designing safer chemicals is challenging. [The Green Chemistry Commitment is a great place to start!] DeVito discusses the need for “toxicological chemists” which would be analogous to medicinal chemists, but instead produce non-toxic commercial chemicals. Medicinal chemists have the training to design appropriate pharmaceuticals, however commercial chemicals do not receive the same attention in terms of designing safe and efficacious products. Since humans are exposed to the commercial chemicals as well, often in intimate settings, the same attention to detail should be used during the synthetic process in order to produce safe chemicals.

Synthetic organic chemists are the ones designing the new chemicals, and we can no longer keep traditional chemists and toxicologists an arm’s length apart. Instead, there is a need for a new type of scientist that considers the function of the chemical for its desired usage and its toxicity potential to humans and the environment. Similar to the training of medicinal chemists, these chemists should receive training in biochemistry, pharmacology and toxicology, and also in environmental fate processes. DeVito suggests adding topics into an undergraduate curriculum, some of which are highlighted here:

  • Limit bioavailability: A common way to prevent toxicity has been to reduce the bioavailability of molecules. Essentially, the idea is that if the chemical cannot be absorbed into the bloodstream of humans or other species, it will not be able to cause significant toxic effects. A common predictor for bioavailability is the “Rule of 5”, where a molecule will have poor absorption if it contains more than five hydrogen bond donors or 10 hydrogen bond acceptors, a molecular weight of more than 500 amu, and a logP (or log Kow) of greater than 5.4 More sophisticated prediction methods also exist based on linear free energy relationships. A good example of low bioavailability is the artificial sweetener sucralose, where only 15% of the chemical is absorbed through the gastrointestinal tract into the bloodstream.5
  • Isosteric substitutions of molecular substituents: By removing parts of the molecule and replacing it with another functional group with similar physical and chemical properties (isosteric) toxicity can be reduced. This is common in medicinal chemistry, where it is referred to as bioisosterism, and is used to reduce toxicity, alter bioavailability and metabolism. A simple substitution can be replacing a hydrogen atom for a fluorine atom, but there can also be much larger isosteric substitutions.
  • Designing for degradation: A toxic molecule that persists in the environment can lead to global long term exposure. Understanding common environmental breakdown mechanisms can allow us to design molecules that will break down to innocuous products after their desired usage. A good starting point is understanding aerobic microbial degradation, since most of our waste ends up at a wastewater treatment plant. An important thing to keep in mind is that if a non-toxic molecule degrades to a toxic molecule, the starting material will still be of concern.

Toxicity is complicated. The best way to arm the next generation of chemists with the skills needed to design smart, safe chemicals is to tailor the undergraduate education to our new goals.

Numerous institutions, including the University of Toronto, are working towards this by signing onto the Green Chemistry Commitment!

(1)         DeVito, S. C. On the design of safer chemicals: a path forward. Green Chem. 2016, 18 (16), 4332–4347.

(2)         Coish, P.; Brooks, B. W.; Gallagher, E. P.; Kavanagh, T. J.; Voutchkova-Kostal, A.; Zimmerman, J. B.; Anastas, P. T. Current Status and Future Challenges in Molecular Design for Reduced Hazard. ACS Sustain. Chem. Eng. 2016, 4, 5900–5906.

(3)         Jackson, W. R.; Campi, E. M.; Hearn, M. T. W.; Collins, T. J.; Voutchkova-Kostal, A. M.; Kostal, J.; Connors, K. A.; Brooks, B. W.; Anastas, P. T.; Zimmerman, J. B.; et al. Closing Pandora’s box: chemical products should be designed to preserve efficacy of function while reducing toxicity. Green Chem. 2016, 18 (15), 4140–4144.

(4)         Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development setting. Adv. Drug Deliv. Rev. 2001, 46, 3–26.

(5)         Roberts, A.; Renwick, A. G.; Sims, J.; Snodin, D. J. Sucralose metabolism and pharmacokinetics in man. Food Chem. Toxicol. 2000, 38, 31–41.