Doing chemistry is very much like commitments in economic activities: the ultimate aim to minimize COST. One of the most iconic aspects of a chemical reaction is the combination of a number of reactants (the players in the reaction flasks, A and B, Figure 1) to afford a number of products (C, D ,E). We are all happy because the equation is balanced.
A + B --------- > C [+ D + E ]
where A, B = reactants
C = desired product
D, E = unwanted WASTES
Figure 1. A normal chemical reaction.
Now focus on the right hand side of the equation, which is the interesting aspect as it is why doing the chemistry at first place. Compound C is indeed the target we want, and the mission is accomplished. However, the watchful readers will be uncomfortable to observe the acquaintance of 2 further compounds, namely D and E. We will assume in this discussion that D and E are not any desired products and of no further uses . In other words, D and E represent the WASTES generated through the reaction between A and B. The nature of the waste is diverse: it can be water, a gas, or even worse, an organic compound (with substantial carbon content). The problem with this seemingly inevitable result is the efforts required to get rid of these undesirable bystanders – which is done practically in the workup and purification stages in a chemical experiment - can be enormous. Not only these represent an investment in much time and effort, the creation of (toxic) waste also provides a longterm impact to the
environment, against the realm of
Green Chemistry. Worse still, the removal of such wastes from our desired product can be tricky sometimes (vide infra).
This situation is best illustrated by examples. Assume compound A and B (Figure 2) react to give our desirable compound C. A combination of
18 carbon atoms end up giving only
7 carbons in our product C - which means
we are destined to lose 11 carbon atoms, and we can’t avoid it. An analogy is that you put 1kg of flour into a bread-making machine (if there exists one of this goodies out there) and ends up getting
5g of bread out, as the rest was burnt up in the machine. What a waste!
A + B --------- > C [+ D + E …]
where A = 6 carbons
B = 12 carbons
Product C only has 7 carbons , waste = 11 carbons!!
Figure 2. A reaction which is NOT very atom-ceonomical.
The ideal outcome we want is: if we have invested 18 carbon atoms in the reactions, we want
all 18 atoms on the target molecule we desire – and we have lost and wasted nothing (Figure 3).
A + B --------- > C
where A = 6 carbons
B = 12 carbons
Product C has 18 carbons, Waste = 0 carbons!! [you has lost nothing]
Figure 3. An atom-economical reaction.
A real example that nicely illustrates this notion is a modern classic, the Wittig reaction, FOR which Prof. Georg Wittig was awarded the Nobel Prize in Chemistry in 1979. It can be said to serve as the ultimate solution to make an alkene (carbon-carbon double bondS) with controllable stereochemical outcomes (E/Z isomers). Looking at the reaction, a worrying aspect becomes apparent (Figure 4).
Figure 4. A real reaction (Wittig reaction) in action. Notice the rightmost phosphorus compound is a pretty nuisance. (adapted from Wikipedia)
It is that legendary phosphorus compound, triphenylphosphine oxide (Ph3P=O, MW – 278.29g/mol !!) that attracts the siren: doing the reaction leads to the desired alkene and the
concomitant formation of triphenylphosphine oxide (
18 carbon atoms, 1 phosphorus, 1 oxygen), and unfortunately the mechanism of the reaction dictates that there is no way you can avoid this phosphorus fella. If we include the carbon atoms on the phosphorus in our calculations , that means we will lose no less than 18 carbon atoms at the end. Worse still, the removal of triphenylphosphine oxide can be very tricky in most cases. If you are not convinced, ask anyone who has done a normal Wittig / Mitsunobu reaction before.
Therefore the type of reaction we are aiming for are those represented by the reactions that follow. This can somewhat ensure the minimal efforts and waste generated as a result. Indeed, Prof. Barry Trost, a famous organic chemistry professor in Stanford, suggested the concept of atom economy about 2 decades ago[1]. His group has also been committing to develop novel reactions that embraces this important philosophy, something that will contribute towards the notion of
Green Chemistry. Some of the following examples are illustrative.
1. ISOMERIZATIONSOne of the most obvious ways not to lose carbon atoms is an isomerization reaction. Isomers of the same compound have the same carbon counts but they differ in their structural arrangements. Thus an
isomerization can cause a subtle change in the molecular skeleton, yet it will not change the number of carbon atoms present – so
everything is conserved. Even if the structure of the molecular skeletons are relatively similar before and after the reaction, differences can still occur as the ‘movement’ of the functional groups, that signify the chemical compound’s ‘behaviour’ , can re-organize to something totally different. Many of these examples can be termed as ‘redox isomerizations’ since we are fiddling with the oxidation states of the compounds. The mechanism often involves acid / base concepts and proton transfers (which has found plenty of parallels in biological mechanisms). Since many of these reactions may require a harsh temperature to be realized,
transition metal catalysis comes to rescue. For example Trost has used his Ruthenium complex to effect a number of redox isomerizations in different organic substrates in a totally atom-economical manner (Figure 5)[2.3]. Note the intriguing design in the first reaction scheme in Figure 5 [2]. Through the isomerization reaction, a propargylic alcohol (alkyne next to a hydroxyl) is ‘switched’ to a,b-unsaturated aldehyde, which then reacts in tandem with a nucleophilic hydroxyl to the oxygen ring in an efficient reaction (Figure 5, above). This represents some form of a
‘reactivity switch’ – once the functional group is switched ON (the Michael acceptor), it reacts nicely. Indeed, the brilliance behind Trost’s work is that by using one type of Ruthenium catalyst, some 20 diverse types of reactivities can be entrained – and all are atom-economical[4].
Figure 5. Redox Isomerizations by Trost et. al. (adapted from Ref. [2] and [3]).
Figure 6. The many faces of isomerization reactions. (adapted from Ref. [5])
The importance of these types of reactions (Figure 6), [5] has been nicely discussed in a perspective article in , rather interestingly, Daltons Transactions lately, since it is focused on possibilities in transition metal catalysis. All these reactions are totally atom economical and, from the article one is easily surmised that the diverse opportunities these methodolgies can deliver. An equally intriguing reaction is the Meyer-Schuster reaction (Figure 7), [5], which has also be implied in the biosynthesis of some fragrant norisoprenoids, including damascenone, a ‘rose-fragrant’ compound that contributes to the nice taste in red wines [6]. It was proposed that the diverse biosynthetic precursors undergo the Meyer-Schuster reaction towards damascenone.
Figure 7. The Meyer-Schuster Reaction (adapted from Ref. [5]).
Figure 8. Damascenone (adapted from Wikipedia).
2. COUPLING REACTIONSCoupling reaction is a form of
molecular LEGO. It involves assembling 2 bricks , reactant A and B, and becomes the product A-B. In normal cirsumstances it will the lead to loss the of a halogen atom (via oxidative addition), and also the metal fragments on its coupling partner. Yet look at Trost’s type of coupling reactions (Figure 9,) [7] - again with complete atom economy. The mechanism is also interesting as they involve some ‘ruthenacycle’ (ruthenium ring) intermediates, which is rather unorthodox for normal cross-coupling reactions [4,7].
Figure 9. An alkene -alkyne coupling reaction. (Adapted from Ref. [7]).
Another great example to cite is Prof. M.J. Krische’s work on C-C coupling reactions (Figure 10), [8,9]. Not only these methodologies are atom-economical, the fantastic aspect is how they play with the
oxidation states of reactants. In normal cases, the correct oxidation state for the reactants to become an alcohol product is that of aldehyde or ketone (C=O). Yet they succeeded in submitting a reactant with a ‘wrong’ oxidation level (an alcohol, C-OH) to afford the product under Ir, Ru, or Rh catalysis. Presumably the alcohol substate is oxidized through the catalysis to generate the ‘right’ oxidation state (C=O) for the reaction to occur. The concept is reminiscent of putting 2 ‘chemical bricks’ together, and can also be rewarded with an impressive
enantioselectivity (>90%e.e.)
Figure 10. Krische-type C-C coupling reactions. (Adapted from Ref. [8,9]).
ConclusionIt is obvious that , at least on an environmental perspective, working towards new reactions which are atom-economical is a clear long-term goal. Not only this will require the creativity of chemists, in many cases we need to draw a lot of inspirations from
Nature, the ultimate synthetic chemist of all.
IN SHORT:
*A reaction which is not atom-economical is a waste of resources, efforts and often has negative impacts on the environment.
*Atom-economical chemical convertions can often be achieved through careful designs, and in many cases we do need inspirations from Nature. Isomerizations serve as a nice example, it is like moving something (the functional groups) on a track (molecular skeleton) with a defined number of components (the carbon atoms), without throwing any of them away in the end.
*In some cases, coupling reactions can be atom-economical too.
by Ed Law 13/06/2010 References:
1. (a) Barry M. Trost (1991) Science , 254, 1471 ; (b) Barry M. Trost (1995) Angew. Chem. Int. Ed. Engl. 34 (3): 259–281.
2.Barry M. Trost, Alicia C. Gutierrez and Robert C. Livingston
Org. Lett., 2009, 11 (12), pp 2539–2542.
3. Barry M. Trost and Robert C. Livingston
J. Am. Chem. Soc., 2008, 130 (36), pp 11970–11978
4. Barry M. Trost
Acc. Chem. Res., 2002, 35 (9), pp 695–705
5. Victorio Cadierno, Pascale Crochet, Sergio E. García-Garrido, José Gimeno
Dalton Trans., 2010, (17),4015-4031
6. Andrew L. Waterhouse, Susan E. Ebeler. Chemistry of Wine Flavor (1998).
7. Barry M. Trost and Alicia Martos-Redruejo
Org. Lett., 2009, 11 (5), pp 1071–1074
8. Soo Bong Han, Xin Gao and Michael J. Krische
J. Am. Chem. Soc., Articles ASAP (As Soon As Publishable)
9. Hoon Han and Michael J. Krische
Org. Lett., 2010, 12 (12), pp 2844–2846
Also see:
http://en.wikipedia.org/wiki/Atom_economy
