theoretical chemistry - Catalyst discovery

How are catalysts for chemical reactions found?

Given a hoped for reaction, let's take the hydrogenation of carbon monoxide to methanol as an example, do chemists:

1. Proceed directly from some property of the reactants to an obvious (to the initiated) catalyst according to some grand unified theory of chemistry


2. Perform a computerized search over some set of simulations of different catalyzed reactions


3. Proceed by trial and error, trying different catalysts in the lab and hoping to find a good one


4. Proceed by trial and error but informed by some negative criteria. "Obviously, the catalyst can't contain [element] because [reason]"

And given a proposed catalyst how much can a chemist predict about the reaction. Would the optimal temperature and pressure be calculable?

Answer

All of the paths given by the OP can lead to discovery of catalysts. Usually, it is a combination of strategies and an accumulation of knowledge from different sources. I will give two examples, ammonia synthesis and enzymatic reactions.

Ammonia synthesis

$$\ce{N2(g) + 3H2(g) <=> 3NH3(g)}$$ The synthesis of ammonia from the elements is one of the largest scale reactions nowadays, and it provides most of the fixed nitrogen (i.e. other than elemental) for human food globally (some nitrogen is fixed by bacteria, especially in roots of legumes). In this sketch, I am using "Ammonia Synthesis Catalysts: Innovation And Practice" by Liu Huazhang as one of the sources. There is also a wikipedia article on one of the players, Alwin Mittasch, that I used.

Fritz Haber figured out that high pressure and low temperature would give the best yield for the reaction (as it is exothermic and the number of gas molecules decreases). This provided the "negative criteria", point 4 made by the OP: the catalyst has to be stable at high pressure. He developed a circulating process to enrich the product and received a patent for it in 1908. Haber and Bosch, working for the BASF company, brought this to industrial scale in the early 1900s, resulting in the Haber-Bosch process. To find a catalyst, they screened thousands of potential substances (strategy 3 given by the OP). They found an efficient osmium catalyist, but osmium was to expensive for commercial use.

The next improvement was a combination of serendipity and rational followup. Mittasch and Wolf, both working for Bosch, were key players. Wolf tried a magnetite from Gallivare, Sweden, that had been "sitting on a shelf" as a catalyst, and it showed promise. There were earlier observations that iron is a good catalyst, but pure iron did not work. Mittasch systematically followed up, figuring out how to reproduce the result by making a catalyst from $\ce{Fe3O4, K2O, CaO, Al2O3 and SiO2}$.

This catalyst, with minor modifications, is still used today. Haber and Bosch won the Nobel prize in 1918, and Ertl won the Nobel prize in 2007 for elucidating the molecular mechanism of the catalysis. Research is ongoing to find other paths to nitrogen fixation (see e.g. here), using other catalysts inspired by biological nitrogen fixation or different precursors (e.g. nitrogen and water for photocatalytical synthesis of ammonia).

Enzymatic catalysis

Enzymes have been developed by trial and error in the course of evolution. It is thought that often enzymes catalyzing on particular reaction led to related enzymes that catalyze related reactions.

A rational way to find a protein that catalyzes a given reaction is to make a transition-state analog. Then, you raise antibodies against that analog. In theory, the antibodies should act as catalysts for the desired reaction, and often they do (catalytic antibodies). This might be the best example of strategy 1 given by the OP.

In 2018, Frances Arnold was awarded a Nobel prize for directed evolution. She was able to mutate known enzymes (or more generally proteins) to catalyze reactions that have no known counterpart in biological systems (for example making carbon-silicon bonds). The process is rational (as in having a plan) but involves randomization and screening steps.

How are catalysts for chemical reactions found?

The answer is all of the above.