Beyond the Numbers: Charting Chemical Reaction Space

Abstract

We present here an informed estimate of the millions of parameter settings that might be required to optimise one typical transition-metal-catalysed reaction. We describe briefly how both Design of Experiments (DoE) and Principal Component Analysis (PCA) techniques may be combined to reduce the number of potential reaction settings to a practical number of experiments without losing critical information. A key feature of this approach is the ability to relate discrete or discontinuous parameters to one another. The methodology is presented so that any reaction may be assessed in a similar way. We believe this represents for the first time an informed estimate of the number of potential permutations that are possible for these types of reactions in particular, and therefore the enormity of the task in optimising them. The powerful combination of DoE and PCA applied systematically and in an experimentally directed approach is beneficial for optimising reactions, particularly challenging transition-metal-catalysed reactions. However, this approach is beneficial to all reactions, especially when dealing with discrete parameters, such as solvents for example.

Development and Optimization of Simple One‐Step Methods for the Synthesis of 4‐Amino‐Substituted 1,8‐Naphthalimides

“…Hence, NMP was the solvent of choice in the synthesis of 4‐morpholino‐substituted 1,8‐naphthalimide 5 , and DMSO in the synthesis of 4‐morpholino‐substituted 1,8‐naphthalimide 6 . We then used statistical experimental design20–24 to optimize the reaction of 4‐morpholino‐substituted 1,8‐naphthalimide 5 . By varying the temperature (150, 175, and 200 °C), reaction time (60, 90, and 120 min), and equivalents of substrates (1:1:1, 1:1:2, 1:2:1, and 1:2:2 ratio of 1 / 4 / 2 ), and measuring yield as a response, a D‐optimal design25 with 25 experimental runs (i.e., 22 different experiments and three replicates) were created using MODDE software 9.1.1.0 (MKS Umetrics AB, Sweden); the results are shown in Table 2 and Figure 2.…”

Efficient Synthesis of 2‐Substituted Phthalimides from Phthalic Acids in One Step

“…The use of trifluoroacetic acid in acetonitrile gave high conversion, but unfortunately also led to the formation of byproducts, whereas the use of acetic acid as solvent proved to be the most promising of the evaluated acidic conditions, and pyridine as solvent was found to provide the most effective basic condi- Next, statistical experimental design [17][18][19][20][21] was employed to optimize the reaction under different conditions. Various acids (acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, and pyridinium p-toluenesulfonate) were next evaluated in different amounts and solvents.…”

Ligand and solvent selection in challenging catalytic reactions

“…solvent) essentially results in a different reaction because every single metal/ligand/solvent combination is effectively a different catalyst system, albeit for the same reaction. This means there are an especially large number of permutations possible for transition metal catalysed reactions …”

“…This is particularly the case for homogeneous catalysis because of the large number of parameters that can be controlled or varied in this type of catalytic reaction. Indeed, we recently published a study which demonstrated just how many permutations there can be for a single catalytic reaction, even with the same pair of substrates . Typical parameters for a catalytic reaction are listed in Table in two groups, continuous and discrete (or discontinuous) parameters.…”

“…Indeed, we recently published a study which demonstrated just how many permutations there can be for a single catalytic reaction, even with the same pair of substrates. 1 Typical parameters for a catalytic reaction are listed in Table 1 in two groups, continuous and discrete (or discontinuous) parameters.…”