C-H Olefination of Monoarylated Cyclobutane 14 to the All-Cis Cyclobutane 16

Complete Arrow Pushing Mechanism:

a: The broad singlet with just one hydrogen at 10.03 ppm indicates that it is bonded to a halogen group, in this case the N-H group.

b: An aromatic hydrogen shift typically falls around 6.5 - 8.5 ppm. The electronegative Nitrogen in the ring deshields these hydrogens, making its shift the furthest downfield.

c, d, f, g, j: Aromatic hydrogen shifts typically fall around 6.5 - 8.5 ppm. They also have corresponding coupling constants, indicating that these protons are coupled in the same ring.

e, i, k: The shift at 7.55 - 7.40 ppm is an aromatic hydrogen. There are two hydrogens because they are almost identical on the two different rings.

h: The shift at 6.92 ppm has a coupling constant of 15.7 Hz for one of its J values. Therefore, it is likely one of the trans coupled protons. It is also has another 3-bond neighbor, indicated that it is the trans coupled proton that is also neighbored with p, J = 9.9 Hz

l: The shift at 6.92 ppm has a coupling constant of 15.7 Hz for one of its J values. Therefore, it is likely one of the trans coupled protons. This proton only has one 3-bond neighbor so it is the trans coupled proton that is only a doublet, not a doublet of doublets.

m, n: The shifts 5.91 and 5.89 are so close together, indicating that they are diastereotopic hydrogens, that are two-bond neighbors, bonded to the same carbon.

o: The shift at 5.85 is a singlet, as there are no neighbors. There are 2 hydrogens there, giving it a 2H integration, and the oxygen is deshielding these hydrogens, shifting the peak downfield.

p: The shift at 4.38 is coupled with proton h, because they have the same J values. It is also a doublet of doublets because of the two differing neighbors and coupling constants.

q: The shift at 4.15 - 4.06 ppm has a very close shift to p because they are bonded to almost identical groups. There is only one hydrogen and it is a multiplet because of the various similar interacting neighboring hydrogens.

r: The shift at 3.95 - 3.87 ppm corresponds to two different hydrogens. The two hydrogens marked r are almost identical in their bonding with carbonyl groups and their coupling is a multiplet due to the various similar interacting neighboring hydrogens.

s: The shift at 3.50 ppm corresponds to the only methyl group in the compound. It is shifted downfield due to the CO₂ group attached to the same carbon and appears as a singlet.

Molecule 14 (480 mg, 1.19 mmol), Pd(OAc)₂ (40 mg, 0.18 mmol, 0.15 eq), AgOAc (298 mg, 1.78 mmol), and 3,4-(methylenedioxy)styrenyl iodide (2.62 g, 10.56 mmol, 3 eq) were mixed in a tube. Under ambient conditions, 5.9 ml of toluene (0.2 M) was added, the tube was sealed, and placed into an oil bath for 10 hours at 80 ^oC. The solution was cooled to room temperature and DCM (10 ml) was added. The solution was filtered through celite and concentrated under vacuum. Silica gel chromatography (3% to 4 % Ethyl acetate in toluene) purified the orange oil, giving molecule 16 (386 mg, 59%) as yellow foam.

Mechanism Related Sources:

These were cited by our article:

Barton D. H. R.; Hesse, R. H.; Wilshire, C.; Pechet, M. M. J. Chem. Soc. Perkin Trans. 1, 1977, 9, 1075 - 1079.

Pelletier, G.; Bechara, W.S; Charette, A. B. J. Am. Chem. Soc., 2010, 132, 12817 - 12819.

Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc., 2005, 127, 13154 - 13155.

“Highly Regioselective Arylation of sp³ C-H Bonds Catalyzed by Palladium Acetate,” was an incredibly helpful journal article to explain our mechanism. Pyridine tethered to an aromatic compound as a directing group, which creates a complexation between Palladium and Nitrogen, is observed in an analogous fashion in, “Sequential Csp³H Arylation and Olefination: Total Synthesis of the Proposed Structure of Pipercyclobutanamide A*.” In addition, the reaction conditions in both articles are similar, allowing us to explain our mechanism in the most detail possible.

This article does an arylation of methylene C-H bonds using palladium (II/IV) catalysts. Our paper was useful because of a similar use of a palladium catalyst in a C-H bond olefination reaction.

Pearson, R.; Zhang, S.; He, G.; Edwards, N.; Chen, G. Beilstein J. Org. Chem., 2013, 9, 891 - 899.

This article uses a picolinamide (PA) group as a directing group for a Pd-catalyzed C-H functionalization reaction. Our particular reaction also uses a picolinamide directing group for the reaction.

Wasa, M.; Chan, K.S.L.; Zhang, X.; He, J.; Miura, M.; Yu, J. J. Am. Chem. Soc., 2012, 134, 18570 - 18572.

This article referenced the insertion of the Pd into a C-H bond with the requirement of a directing group such as pyridine. Our reaction used a palladium catalyst with a similar directing group, picolinamide, to undergo a C-H ligand directed reaction.

Q: Explain why 16 is formed as a single diastereomer.

A: The reaction with the Pd catalyst at the C-H bond is more stable in the transition state that contains the very bulky substituents in an anti-position, because of sterics. This suggests that in order for the C-H bond to be cleaved, there must be a minimum dihedral angle between the C-H bond and the Pd-OAc bond that exists in the transition state. This transition state subsequently allows the reaction to continue, thus forming the single diastereomer in our product 16.

Giri, R.; Lan, Y.; Liu, P.; Houk, K.N.; Yu, J. J. Am. Chem. Soc., 2012, 134, 14118 - 14126.

Evan Dahan

Evan Dahan was orginally cast to play the role of Jesse Pinkman in America's hit T.V. series, "Breaking Bad." Unfortunately, Aaron Paul's late audition tape won the hearts of the casting agents. This caused Evan Dahan to have a complete mental breakdown and drove him to fully emulate Jesse Pinkman. Last year, Evan's meth cooking operation was busted, and he is now serving a life sentence without parole at the Penitentiary of New Mexico.

Audrey Niemchick

Audrey is a 6 time award winning play-doh sculptor by day and crime fighting Batgirl by night. She prowls the streets of Gotham protecting the citizens from the wrath of evil-doers while bringing delight with her doughy creations. She also enjoys smiling, puppies and long walks on the beach.

James Rhee

Born and raised in south Detroit, James has worked for NASA for 10 years, has traveled to Mars, and established surviving colonies. Currently, he studies organic chemistry at the University of Michigan, Ann Arbor to discover the chemical compositions of possible extraterrestrial life on potential habitable planets. His ambitions are to establish a base on Jupiter's moons and visit pluto in the near future. In his free time, he loves to play Super Smash Brothers Melee/Brawl and basketball with his family and friends.

Starting material:

Soluble in many organic solvents, palladium (II) acetate is a brownish-yellow solid that acts as a catalyst in many organic reactions. Molecular formula is C₄H₆O₄Pd, melting point is 205 ^oC, and molar mass is 224.50 g/mol. In this experiment, palladium inserts between carbon iodide bond in molecule 15 and complexes with molecule 14.

A white, crystalline solid that has the empirical formula, AgC₂H₃O₂. Anti-smoking products have used silver acetate to deter smokers from smoking. In this experiment, silver acetate is used as a solvent in the reaction and acts as a base and conjugate acid.

Starting material:

An aromatic hydrocarbon with the smell of paint thinners. A colorless liquid that is commonly used as an organic solvent, it has intoxicating properties. In this experiment, toluene is used as a solvent.

Laboratory device used to heat a reaction using heated oil.

Colorless, volatile liquid with molecular formula of CH₂Cl₂ that is commonly used as an organic solvent for its ability to dissolve a variety of organic compounds. In this case, it is used as a solvent.

Used as a filtration aid to separate fine precipitate for its high porosity. Prevents filter paper from getting clogged and precipitate from passing through. Hollow, microscopic particles of fossilized remains of diatoms.

A paste is formed by mixing the solvent with celite. The paste is filtered through a Hirsch or Buchner funnel until a thin layer is formed on the filter paper. The solvent in which celite was mixed is removed from the filter flask. Before the filtration process, the filter flask is cleaned.

Silica gel is a hard, polar form of silicon dioxide, made from sodium silicate. It is useful in creating separating based on interactions with the hydrogen bond capable water molecule in the silanol group that interacts with polar and hydrogen bond capable compounds. Chromatography involves using a tube and silica gel to separate and purify different compounds in a mixture based these polarity and size differences. A stationary phase, such as a slurry of silica gel mixture, is inserted at the base of the tube to keep the silica in the tube and the solvent is added to wet this stationary phase. The organic layer is pipetted onto the top, and topped with cotton or sand so it does not all run with the solvent. The solvent (typically hexane and ethyl acetate) is consistently added and passes through the column so that the organic material can be obtained at the bottom. This eluent is collected in fractions and each fraction is analyzed for dissolved organic compounds.

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