In the Laboratory edited by The Microscale Laboratory Arden P Zipp SUNY Cortland Cortland NY 13045 An Organic Puzzle Using Meldrum s Acid W R David Crouch and Michael S Holden Department of Chemistry Dickinson College Carlisle PA 17013 2896 crouch dickinson edu holden dickinson edu Numerous articles in this Journal have lamented the cookbook nature of undergraduate organic labs 1 4 Such experiments bear little resemblance to true organic research students simply follow a recipe to make a product that can often be predicted by simply reading the textbook 3 By contrast experiments that generate products not easily predicted by students require identification through analysis of data and a consideration of the possible reactions of the reagents and solvent 2 4 Experiments of this nature enhance students analytical and problem solving skills 2 while providing a more accurate portrayal of true organic chemistry In this paper we wish to add a lab exercise to the growing body of organic puzzles that promote these principles Background Despite its name Meldrum s acid 1 or 2 2 dimethyl1 3 dioxane 4 6 dione is not a carboxylic acid 5 But the methylene hydrogens are unusually acidic 6 8 and the conjugate base can undergo reactions with electrophiles such as formaldehyde 9 The resulting Knoevenagel condensation1 product 3 is a potent Michael acceptor and under these conditions Michael addition of a second molecule of Meldrum s acid occurs to yield the product diisopropylidene methylenedimalonate 4 The mechanism of a tandem Knoevenagel Michael reaction makes this an ideal experimental puzzle for the end of a unit on enol and enolate chemistry O O O O HCHO OH O H O O O 1 2 Although other aldehydes might be useful in this reaction the lengthy reaction times required preclude their use in 3to 4 hour lab sessions Also an important solvent effect was reported when other aldehydes were used For example when benzaldehyde replaced formaldehyde a significant amount of Knoevenagel condensation product but no Michael adduct was isolated when DMSO or glacial acetic acid was used in place of DMF implying that Michael addition is more favorable in DMF 9 Similar results were reported for other aldehydes Experimental Procedure To a 3 mL conical vial containing a stir vane was added 144 mg 1 0 mmol of 2 2 dimethyl 1 3 dioxane 4 6 dione and 200 L of DMF The mixture was stirred until the solid had dissolved and 38 L 0 50 mmol of 37 aqueous formaldehyde was then added The flask was capped and stirring was maintained for 90 min during which time a solid formed The flask was uncapped 500 L of water was added and the mixture was cooled in an ice water bath for 15 min The solid was collected by filtration on a Hirsch funnel and rinsed with a minimum amount of cold water to yield 128 mg of diisopropylidene methylenedimalonate 4 85 as a white solid mp 143 145 C lit mp 144 5 146 C 9 1H NMR CDCl3 4 53 t J 1 76 Hz 2H 2 79 t J 1 76 Hz 2H 1 84 s 6H 1 79 s 6H 13C NMR CDCl3 165 4 105 7 42 5 24 5 26 4 23 2 Student yields ranged from 29 to 97 with an average of 57 The reaction time can be shortened by heating the same mixture to 65 70 C for 45 minutes and following the same workup protocol However the formation of white solid in the reaction vessel which provides visual evidence of a reaction is not observed under these conditions and yields are considerably lower than in the room temperature reaction O O CH2 O Formaldehyde is a lachrymator and suspected carcinogen DMF is an irritant and teratogen However concerns about the safety of using formaldehyde and DMF are minimized by the small scale of the reaction O 3 1 O O O Hazards O CH2 O O O O 4 Discussion The exact mechanism of this reaction is not clear One can envision a mechanism involving either an enol or an JChemEd chem wisc edu Vol 79 No 4 April 2002 Journal of Chemical Education 477 In the Laboratory enolate of Meldrum s acid as the nucleophile However Arnett has shown that Meldrum s acid is not appreciably enolized in solution less than 5 is in the enol form 8 On the other hand the base needed for most enolate reactions is not used in this reaction But Meldrum s acid does condense with formaldehyde in polar solvents such as DMF 9 and clearly one of these two mechanisms is followed We allow students to develop either mechanism and feel this exercise highlights the fact that not all questions in organic chemistry have been answered The symmetry of the final product leads to a strikingly simple NMR spectrum with hydrogens on different carbons appearing at the same chemical shift a subtlety that catches many students off guard Additional information however can be gathered by considering how Meldrum s acid might interact with formaldehyde Most students will recognize that Meldrum s acid is similar to the more familiar malonate esters What kinds of reactions might a malonate ester and formaldehyde undergo Is an aldol reaction or a Knoevenagel condensation more likely Does the NMR spectrum agree with the product of either of these reactions Does either reaction lead to a molecule that is unlikely to react further Most students recognize that neither reaction product 2 nor 3 is consistent with the NMR spectrum but that the methylene malonate 3 formed via a Knoevenagel condensation could go on to react with another molecule of Meldrum s acid This possibility and the reaction stoichiometry 2 1 Meldrum s acid formaldehyde lead most students to identify the correct product 4 which is consistent with the NMR spectrum This lab exercise produces a product that students cannot immediately predict But they can identify the product using its NMR spectrum and knowledge of reactions covered in most sophomore organic courses The experiment can be performed using glassware that is typically available in an undergraduate organic laboratory 478 W Supplemental Material Notes for the instructor a handout for students and some sample spectra are available in this issue of JCE Online Note 1 The term Knoevenagel condensation is used here to describe condensations of active methylene compounds with aldehydes and ketones 10 The classical Knoevenagel condensation however requires an amine base and the mechanism involves formation of an iminium ion that is attacked by the conjugate base of the active methylene compound 11 In the reaction described here the socalled Hann Lapworth mechanism is invoked 11 Literature Cited 1 All of the following are in J Chem Educ Pickering M 1985 62 874 1990 67 524