Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017 Diels-Alder reaction of N-phenylmaleimide with in situ generated buta-1,3- diene Supplementary Material Notes: This work is planned for two sessions of 3 h each in a laboratory equipped with two rotary evaporators. It has been offered as a laboratory classroom work, for more than four years, to second year undergraduate chemistry students (about 30 students a year, in classes of 16 students, working in groups of two). Students are challenged to synthesize a Diels-Alder cycloadduct. The experimental work illustrates a cycloaddition reaction between a conjugated diene (buta-1,3-diene), generated in situ by thermal extrusion of SO2 from 3-sulfolene, and N-phenylmaleimide. The reaction is performed in refluxing toluene (the oil bath must be kept at a temperature above 120 °C) in order to generate the buta-1,3-diene. Both 3-sulfolene and N-phenylmaleimide are commercial compounds but the N-phenylmaleimide can be prepared previously by the students following the procedure in the experiment entitled “Synthesis of N-arylmaleimides”. The condenser must be refrigerated to avoid the evaporation of the toluene (Figure SM 10.1.2). The reaction may be monitored by TLC. In this case it is necessary to cool down the reactional flask before the removal of the sample to be analysed. Silica gel F254 should be used both in the analytical and preparative TLC; dichloromethane is a good eluent to develop the chromatogram. In the analysis of the crude reaction mixture by TLC, it is recommended the use of the starting N- phenylmaleimide (dissolved in dichloromethane) as reference: the reference and the reaction mixture should be spotted on the TLC plate about 1 cm apart and 1 cm from the bottom. Retention factors (Rf) can be used to confirm the presence of unreacted N-phenylmaleimide in the crude oil. To determine the retention factor, the students should mark with a pencil the solvent front immediately after the removal of the TLC plates from the TLC chamber and outline the spots visualized under the UV-lamp. The cycloadduct has a lower retention factor than N-phenylmaleimide. During the visualization of the TLC plates under the UV-lamp the students must wear safety glasses at all times. The aim of this experiment is to illustrate the formation of a six-membered ring via a cycloaddition reaction. For the characterization of the resulting product by NMR it is just required a small portion of Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017 pure cycloadduct. So, it is not necessary to purify by preparative thin layer chromatography (TLC) all the crude product obtained. The yield of the reaction was always calculated for the crude product (55-65%), since only a small amount was purified by TLC for the NMR analysis. Figure SM 10.1.1 - Reaction setup apparatus. Figure SM 10.1.2 - Filtration apparatus. Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017 1 Figure SM 10.1.3 - H NMR spectrum (300 MHz, CDCl3) of the Diels-Alder cycloadduct. Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017 13 Figure SM 10.1.4 - C NMR spectrum (75 MHz, CDCl3) of the Diels-Allder cycloadduct. 1 Figure SM 10.1.5 - H NMR spectrum (300 MHz, CDCl3) of N-phenylmmaleimide. 13 Figure SM 10.1.6 - C NMR spectrum (75 MHz, CDCl3) of N-phenylmaleimide. Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017 Synthesis of isomeric bicyclopropyls from conjugated dienes Supplementary Material Leiv K. Sydnes, Magne O. Sydnes Recommended study level This experiment is indeed easy to carry out successfully on the condition that the required equipment is available and the students have learnt the basic laboratory operations and can execute them properly. From an experimental point of view the synthesis may therefore be included in a laboratory course at an intermediate level. However, cyclopropane chemistry is oftentimes not incorporated in curricula at this level, a consequence of which is that the experiment may appear somewhat out of context if the purpose of the laboratory course is to illustrate the material covered in the course lectures and the accompanying textbook(s). On the other hand, if the idea is that the practical work should be regarded as a supplement to the theory presented, the synthesis should be considered as an attractive option. The synthesis of 2,2,2’,2’-tetrachloro-3,3,3’,3’-tetramethylbicyclopropyl as presented here has been carried out by students at intermediate and advanced levels a number of times. No serious problems have been observed. Preparations have been carried out on a 15 mmol to 0.10 mol scale, and the isolated yield after recrystallization has ranged from as low as 10% to as high as 93%. (The lowest yields were obtained by students with inferior recrystallization skills, the consequence of which was a significant loss of product.) The colour of the product was not consistent even in successful experiments; in one case it was white, but in most cases it appeared to be yellowish to light brown or somewhat grey (see the picture in the Photo section). The isomeric composition was not always determined accurately, only the melting point was measured consistently, but when analyses were carried out, the ratio was in the 7:3 to 3:1 range in favour of the meso isomer after recrystallization. Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017 The isomeric composition can be determined by both 1H-NMR spectroscopy and GLC analysis (see the section Product data). The compound is too volatile to be analysed by TLC.1 Theory contextualization Cyclopropanes have become quite prominent compounds in organic chemistry the last few decades, both as a structural moiety incorporated to introduce strain in a carbon skeleton, and as intermediates in organic synthesis. In spite of this many chemistry students regard three-membered carbocycles as quite unstable due to strain (about 28 kcal/mol) caused by the ring’s significant deviation from the ideal tetragonal angle. Synthesis of a stable cyclopropane can therefore serve the students beyond giving them practical experience with phase-transfer catalysis which is applied here. The cyclopropane synthesized here is a so-called gem-dichlorocyclopropane. As pointed out in the introduction to the experimental section, a large number of methods are available for the preparation of such compounds.2 The method of choice in a given case depends on several factors, but when the substrate is an alkene without other reactive moieties the Makosza method3,4 appears very attractive. This is the method applied here because it has a number of advantages over most of the alternatives: a) The reaction is carried out under aqueous conditions; b) Only moderate cooling is required (ice/water); c) No heating is necessary; d) The dichlorocarbene precursor, chloroform, is stable, commercially available, and inexpensive; f) No problematic waste is generated. An attractive and educational feature with Makosza’s method is the phase-transfer mechanism by which the dichlorocarbene is formed. As illustrated in Figure SM 10.2.1 (Cl = X) the first reaction (Eq.1) is the equilibrium which was studied by Hine,5 but which under aqueous conditions, in the absence of an organic phase and an ammonium ion, furnishes dichlorocarbene that reacts rapidly with water and/or hydroxide and forms formate and carbon monoxide. In the presence the triethylbenzylammonium ion, however, the ammonium ion replaces the sodium ion and forms a salt (Eq. 2) which dissolves in the organic phase (Eq. 3). Here the salt decomposes and affords Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017 dichlorocarbene (Eq. 4) which reacts with a C=C moiety before any moisture dissolved in the organic phase intervenes; this gives the desired product, the corresponding 1,1-dichlorocyclopropane (Eq. 5). Interphase Eq. 1 CHX3 + NaOH CX3 Na + H2O Eq. 2 CX3 Na + ClNEt3Bz CX3 NEt3Bz + NaCl NaCl (H2O) Eq. 3 CX3 NEt3Bz + NaCl CX3 NEt3Bz (org) Organic phase Eq. 4 CX3 NEt3Bz :CX2 + X NEt3Bz R R Eq. 5 :CX2 + X X Figure SM 10.2.1. The reactions taking place at the interface under phase-transfer cyclopropanation. The cyclopropane formation involves a cheletropic reaction which is one of the fundamental reactions exhibited by singlet carbenes. The reaction can be analyzed by the tools developed by Woodward and Hoffmann,6 but the thorough studies published by Moss and co-workers give deep insight into the nature of the process.7,8 What is important is the interaction between the HOMO and the LUMO orbitals of the reacting species. As depicted in Figure SM 10.2.2 the HOMO-LUMO interactions bring 9,10 the carbene and the alkene together and lead to cyclopropane formation. Cl Carbene LUMO Cl Alkene HOMO Figure SM 10.2.2. One possible HOMO-LUMO interaction between the carbene and the alkene. Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017 There has been no indication whatsoever of formation of 2,2-dichloro-3,3-dimethy-1-(2-methylprop-1- enyl)cyclopropane, the expected mono-adduct from 2,5-dimethyl-2,4-hexadiene, in the preparation of 2,2,2’,2’-tetrachloro-3,3,3’,3’-tetramethylbicyclopropyl. In the synthesis described here that is perhaps that surprising since a significant excess of carbene is applied, but even when an excess of the diene is used only the bis-adduct is obtained.