Sweet clover, moldy

The aldol condensation of 4-hydroxycoumarin with fonnaldehyde provides an a,p-unsaturated carbonyl compound, which then undergoes a conjugate (1,4-) addition of a second molecule of 4-hydroxycoumarin. This reaction could be catalyzed by either trace base or trace acid the acid-catalyzed reaction is shown and discussed here. The enol portion of 4-hydroxycoumarin is the nucleophile in an aldol reaction with protonated formaldehyde. The resulting product dehydrates to provide the a,p-unsaturated carbonyl compound, which, after protonation renders it a more reactive electrophile, then reacts with another nucleophilic molecule of 4-hydroxycoumarin in a conjugate addition reaction. This product, upon loss of a proton to the aqueous solvent, leads to dicoumarol. This substance is present in moldy sweet clover. It is a blood anticoagulant and its ingestion leads to the hemorrhagic sweet clover disease that kills cattle. 

Coumarin glycosides are found throughout the plant kingdom (Burrows and Tyrl, 2001). Seeds of Aesculus glabra (Ohio buckeye) contain the coumarin esculin, which is a mild neurotoxin. Sweet clovers Melilotus spp.) contain coumarins that are considered harmless unless moldy conditions exist, in which fungal activity produces the double coumarin dicoumarol. Dicoumarol is a... 

Dicoumarol is a derivative of coumarin, a cyclic ester that gives sweet clover its pleasant smell. Coumarin, which does not interfere with blood clotting and has been used as a flavoring agent, is converted to dicoumarol as sweet clover becomes moldy. Notice that coumarin is a lactone (cyclic ester), whereas dicoumarol is a dilactone ... 

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