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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Leading by Example in the Lab

Leading by Example in the Lab

By Ian Mallov, Co-Chair for the GCI

Ask a scientist what their greatest satisfaction is from research.  Most will probably tell you something along the lines of “the pursuit and discovery of new knowledge.”

Some will mention the parallel satisfaction of originating inventions or techniques that are broadly applicable, and seeing that work applied for the benefit of society.

Much of the challenge of moving towards a truly sustainable culture is in applying what we’ve already shown to be effective on small scales.

Two years ago, the Green Chemistry Initiative’s 2014 Workshop team developed ten recommendations entitled “Simple Techniques to Make Everyday Lab Work Greener.”  Led by co-founder Laura Hoch, with important contributions from Cookie Cho and Dr. Andy Dicks, we publicized these during the workshop.  So what has happened to these recommendations since?  They’ve been developed – are researchers in our department incorporating them into their work habits?  Are we ourselves applying what we already know to be effective?

I was pleasantly surprised to find out that a number of our researchers were in fact using these greener lab techniques.  In an effort to make their use even more widespread, I’d like to highlight some examples of researchers in our department who are leading by example.

Further, next week our “Simple Techniques to Make Everyday Lab Work Greener” poster will be posted around the department!


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Scientist: Karlee Bamford, Stephan lab

Technique: Recycling solvents from rotovap to use for cleaning vials and glassware

Why it’s greener: Saves solvent, reduces waste generated, and reduces energy used in production and disposal of additional solvent

Issues to Consider: Use in synthesis and purification often requires solvents to be more pure than those collected from rotovap


Ian_July blog 2Scientist: Aleksandra Holownia, Yudin lab

Technique: Setting GC to stand-by mode when not in use

Why it’s greener: The GC uses much less helium gas (a rapidly diminishing resource) and reduces the temperature of the oven, saving energy

Issues to Consider: Does take a few minutes to start up again


Ian_July blog 3Scientist: Karl Demmans, Morris lab

Technique: Using 2-methyl THF as a reaction solvent instead of THF

Why it’s greener: 2-methyl THF is derived from the aldehyde furfural, sourced from renewable crops.  THF, on the other hand, is derived from fossil fuels.  While crop-sourcing does not automatically make it “greener,” consensus in the case 2-methyl THF is that it is indeed less energy- and resource-intensive to produce than THF.

Issues to Consider: Unlike THF, it is immiscible with water.  Slightly less polar than THF


Ian_July blog 4Scientist: James LaFortune, Stephan lab

Technique: Isopropanol/dry ice instead of acetone/dry ice for cold baths

Why it’s greener: An Isopropanol/dry ice bath maintains a temperature of -77 oC, almost exactly the same as acetone/dry ice’s -78 oC.   However, isopropanol is much less volatile (bp: 83 oC) than acetone (bp: 56 oC); practically, this allows for the recovery and reuse of the isopropanol after several hours or overnight, while acetone evaporates.

                                                                          Issues to Consider: Must actually recover and reuse the isopropanol!


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Scientist: Samantha Smith, Morris lab

Technique: Closing the fume hood sash when not in use.

Why it’s greener: Modern, variable-flow fume hoods – used in the Davenport wing of our building – regulate the strength of their vacuum for safety based on how far open the fume hood is.  When wide open, the fume hood uses much more energy than when closed (see Just Shut It campaign!)

Issues to Consider: Is your fume hood variable-flow?

 


Ian_July blog 6Scientist: Brian de la Franier, Thompson lab

Technique: Using a closed-loop cooling system for refluxes and distillations.

Why it’s greener: Uses much less water.  While some of our undergraduate labs have built-in closed-loop cooling systems, Brian simply got a small fish tank pump from a pet store and uses a Styrofoam box with ice to keep his water cold – a very easy DIY solution!

Issues to Consider: Does water saved compensate for the extra energy for the ice/pump?  Consider the energy used to purify and deliver the extra water and we can safely say yes.


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Scientist: Alex Waked, Stephan lab

Technique: Reusing rubber septa used to seal Schlenk flasks

Why it’s greener: Saves materials and money

Issues to Consider: There is a limit to their reusability.  At some point, if a septum has been perforated by too many needle holes it is no longer an effective seal.  Must also ensure septa are kept clean.


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Scientist: Molly Sung, Morris lab

Technique: Reusing gas chromatography vial caps by replacing their septa

Why it’s greener: Saves materials and money

Issues to Consider: Somewhat time-consuming to remove and replace rubber septa for each cap

 


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