trends in reactivity based on substitution of the starting iodoarene 5. 1) Pd(OAc) 2, CH 2 CN 2) HCl O Triethylamine

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1 The eck Reaction Introduction The eck reaction is of great importance, as it results in a carbon- carbon bond through a metal catalyzed coupling reaction 1. The reaction involves an unsaturated halide, a base, and palladium catalyst to produce a substituted alkene 2. The eck reaction is named for its founder Richard eck, who in 2010 was awarded the Nobel Prize in Chemistry for his discovery of the reaction 3. Today, the eck reaction has a wide array of applications, such as the synthesis of morphine (Figure 1), which is an opiate analgesic medication used to alleviate chronic and acute pain 1. Morphine is synthesized via a tandem intramolecular eck insertion (Scheme 1). "#$%&%!'(!)%*#+,-.!"#$%&%!/-0!1*.2%&!!3.+0*&-4%#54*0!6%#7!,.8%0+,-.!+-!89.+$%8,:%!!;-0<$,.%!! trends in reactivity based on substitution of the starting iodoarene 5.!"#$%&'()'*+%$,+$%&'-.'/-%01"2& In this synthesis, 1- iodo- 3- nitrobenzene was reacted with acrylic acid, triethylamine, and palladium acetate to produce trans- 3- nitrocinammic acid. The melting point of the product was obtained and the product was analyzed by infrared spectroscopy (IR) and nuclear magnetic resonance (NMR). Class data was collected to study the electronic and steric effects of the iodoarene substrate to reveal N C 3 I + + Et 3 N 1) Pd(Ac) 2, C 2 CN 2) Cl N 2 Triethylamine 1-iodo-3-nitrobenzene Acrylic acid N 2 trans-3-nitrocinnamic acid!"#$%$&'(&)$*"+,-.&/"#$%$&-0&12, ,+5-6$.7$.$&8,+#&*"59:,"&*",3&+-&;5-3<"$&+5*./242.,+5-",..*%,"&*",3

2 Experimental Synthesis 1- iodo- 3- nitrobenzene (1.26 g, 5.06 mmol), acetonitrile (0.2 ml, 38.5 mmol), triethylamine (0.8 ml), acrylic acid (0.43 ml, 6.25 mmol), and palladium acetate catalyst (.056 g, 0.25 mmol) were added to a 10 ml round- bottomed flask. The reaction flask was refluxed and stirred magnetically in a water bath at 90 C for one hour. Work- up The mixture was allowed to cool and the reaction flask was transferred to a 400- ml flask containing Cl (150 ml, 3M). The crystals were collected by suction filtration and washed with a solution of cold water and methanol (50:50) to yield an orange clay- like product (0. 83 g, 4.30 mmol, 83% yield). The crystals were allowed to dry for 10 minutes. Melting point was found to be C ( C, literature value) 5. Analysis Melting point was found to be C ( C, literature value) 1. The product was used to obtain IR and NMR spectra. A KBr pellet was prepared for IR, and the solvent for NMR was deuterated DMS. Results Table 1: Infrared Spectral Data for trans- 3- nitrocinnamic acid Frequency (cm - 1 ) Bond Functional Group Comment 1614 cm - 1 C=C Aromatic Weak 1634 cm - 1 C=C- 2 Vinyllic Moderate 1698 cm - 1 C= Carbonyl Carboxylic Acid cm Alcohol () Broad 8.18 ppm (1, d) 7.68 ppm (1, t) 7.70 ppm (1, d) 6.70 ppm (1, d) 8.25ppm (1, d) 8.48 ppm (1, s) N 2 Figure 2: Proton NMR assignments for trans- 3- nitrocinnamic acid Table 2: 2010 Class Average Percent Yield Data Name of Substrate Class Ave. Yield % 2- iodoanisole 4.3

3 3- iodoanisole iodoanisole iodotoluene iodotoluene iodotoluene iodonitrobenzene iodonitrobenzene iodonitrobenzene bromoiodobenzene bromoiodobenzene bromoiodobenzene chloroiodobenzene chloroiodobenzene chloroiodobenzene fluoroiodobenzene fluoroiodobenzene fluoroiodobenzene 25.5 Discussion The reaction between 1- iodo- 3- nitrobenzene and acrylic acid with triethylamine, and palladium acetate catalyst produced trans- 3- nitrocinammic acid (Figure 3). The experimental melting point of the product was determined to be C, which differs significantly from the literature value of C 5. This indicates that the product collected was impure and that perhaps the starting material was still present in the product. The product expected to form was trans- 3- nitrocinnamic acid. IR and NMR spectra confirm the structure of the product. IR produced four key peaks (Table 1). The peak at 1614 cm - 1 marks an aromatic ring and the peak at 1634 cm - 1 is characteristic of a C=C bond, the signal is lower than normal because the double bond is conjugated. The peak 1698 cm - 1 is indicative of a conjugated carbonyl, while the peak from cm - 1 is broad and signals an alcohol group. Proton NMR further verifies the structure and identity of the product. Figure 2 shows the proton assignments. The peak at 6.70 ppm is a one hydrogen doublet and it corresponds to the vinylic proton α to the carbonyl. The peak at 7.70 ppm with an integration of 1 and doublet corresponds to the β vinylic hydrogen; it is more downfield since it is deshielded by the carbonyl (Figure 4). The doublet at 8.18 ppm has an integration of 1 and signals the proton para to the nitro- N

4 group, it is deshielded by the nitro group as can be seen by resonance. The 1 triplet at 7.68 ppm signals the proton meta to the nitro- group. The 1 doublet at 8.25 ppm is the proton para to the alkene substituent. The 1 singlet at 8.48 ppm represents the proton between the nitro- group and the alkene substituent. Its signal is really downfield since the adjacent nitro group and alkene substituent are electron withdrawing and thus deshield the proton next to it. Furthermore, proton NMR shows the impurities present in the product. The percent yield for trans- 3- nitrocinnamic acid was 83%, which differs from the class average data of 69%. As NMR indicates there are a lot of impurities in the product, such as water and starting material, which falsely increase the percent yield. This could have been prevented if the product had been recrystallized. The oxidative addition step (Figure 2) is the rate- determining step, and the substituent on the benzene controls the rate. The class data can be separated into two broad groups: electron withdrawing substituent and electron donating substituent. The electron withdrawing groups like the nitro group takes away electron density making the carbon iodine bond more electrophilic, thus the rate of oxidative addition is increased. The electron donating groups such as the methoxy and toluene groups donate electron density and make the carbon iodine bond less electrophilic, thus decreasing the rate of oxidative addition. The molecules with electron withdrawing groups yield higher percent yields because they increase the electrophilic nature of the carbon iodide bond when compared to electron- donating groups, which decrease the electrophilic nature. Another interesting trend is that for molecules with electron withdrawing groups the ortho product had the highest percent yield, while the para product had the lowest, and the meta was between the ortho and para. It is possible that the electron- withdrawing group has a greater effect when the iodine is ortho because it is able to withdraw more electron density and make the carbon iodine bond more electrophilic than when the iodine is in the meta or para position. The para product has the smallest yield because the electron- withdrawing group is farther away. For the iodobenzene with a donating group the opposite happens. That is, the para product produces the highest yield because the donating group has less of an effect on the carbon iodine bond when it is para than meta, and ortho produces the least. The electron- donating group has more of an effect when the iodine is ortho or meta because the electron- donating group is closer to those positions, whereas since it is so far away from the para position it has less of an electron donating effect when compared to ortho and meta.

5 Conclusion The reaction between 1- iodo- 3- nitrobenzene and acrylic acid with triethylamine and palladium acetate produced trans- 3- nitrocinammic acid through the eck reaction. The percent yield for this reaction was 83%, which is higher than the class average due to impurities. The oxidative addition step is the rate determining step and the nitro group affects the rate. Because the nitro group is electron withdrawing it increases the rate- determining step. Reference 1. Link, J. T The Intramolecular eck Reaction. rganic Reactions David Dubuisson, Stephen G. Dennis. The formalin test: A quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats, Pain, Volume 4, ctober April 1978, Pages ( 3. Masunaga, S. Alumnus Richard eck wins Nobel Prize in Chemistry, UCLA Daily Bruin, ctober 13, 2010 (accessed April 2011) 4. Sigma Aldrich, states.html. Accessed December 8, Smith College Moodle, CM 223 All Labs, Fall 2011, Laboratory Exercise 6, The eck Reaction