On the Probability That Ring-Forming Multicomponent
Reactions Are Intrinsically Green: Setting Thresholds for Intrinsic
Greenness Based on Design Strategy and Experimental Reaction Performance
posted on 2013-05-06, 00:00authored byJohn Andraos
This
paper describes in detail the determination of the likelihood
that a given generalized chemical reaction may be considered intrinsically
“green” based on design strategy. Justification is given
for setting threshold constraints on reaction yield and kernel reaction
mass efficiency (RME) performances at greater than 80% and greater
than 61.8%, respectively, for intrinsically green reactions. These
criteria are applied to a survey of 60 named ring-forming multicomponent
reactions (MCRs) and 2000+ such reactions reported in the literature
from 2003 to 2011. Patterns among various ring construction motifs
are discussed. Results show that 5- and 6-membered monocyclic rings
are most commonly made by [2+2+1] and [3+2+1] cycloadditions where
57% and 76% of them, respectively, have a 100% chance of being intrinsically
green from a design perspective. Similarly, the [4.3.0] and [4.4.0]
skeletons are the most common fused bicyclic structures made by MCR
strategies where 38% and 59% of them, respectively, have a 100% chance
of being intrinsically green. The syntheses of various heterocyclic
ring structures made by MCRs have also been surveyed using this new
criterion. The application of this probability analysis is also demonstrated
for the total synthesis of ring containing scaffold structures of
praziquantel and frondosin B, two compounds of pharmaceutical interest
made using MCRs. The direction of future research in MCR development
is also briefly discussed.