IChO 2023 · Theory problem 9

Electrolysis in Organic Synthesis

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The Kolbe electrolysis describes the decarboxylative dimerization of two carboxylic acids and only proceeds if the acid is deprotonated. The unbalanced equation is shown here.

Figure 1

Two gases (B and C) are produced during the reaction. B reacts with \(\ce{Ca(OH)2}\), while C is highly flammable.

9.1 Provide the structural formulae of A, B, and C.

9.2 The synthesis is formally a redox reaction, where the carboxylate is oxidized and the solvent is reduced. Formulate the oxidative and reductive half reactions and the overall redox reaction.

9.3 Provide the intermediates 1 and 2 in the mechanism for the oxidative decarboxylation and formation of the product.

Figure 2

The Kolbe electrolysis is usually only efficient for long-chained saturated carboxylic acids and not for certain carboxylic acids, such as D. Here, the overoxidation of the radical intermediate E to a positively charged species F is facilitated. Intermediate F can react with nucleophiles to form different side products, for example it reacts with D to form an ester G, and with \(\ce{MeOH}\) to form H.

Figure 3

9.4 Provide the structures of D–H.

The electrolysis of carboxylic acid I in the presence of an excess of co-acid J yields two main products (by \({}^{1}\mathrm{H}\) NMR analysis) that are inseparable by silica gel chromatography. Their spectroscopic data are almost identical. In the \({}^{1}\mathrm{H}\) NMR, the two species are only distinguishable by two signals with small differences in chemical shifts.

Figure 4

The \({}^{1}\mathrm{H}\) NMR spectrum looks as follows (1:1 mixture of products K and L):

4.18–4.08 (m, 4 H), 3.95–3.60 (m, 6 H), 3.43 (dt, 2 H, \(J=7.8,\ 2.2\ \mathrm{Hz}\)),
2.55–2.25 (m, 4 H), 2.20–1.95 (m, 2 H), 1.65–1.50 (m, 2 H)

Specific signals for K:

1.26 (t, 3 H, \(J=7.2\ \mathrm{Hz}\)), 1.20 (d, 3 H, \(J=6.6\ \mathrm{Hz}\))

Specific signals for L:

1.24 (t, 3 H, \(J=7.2\ \mathrm{Hz}\)), 1.15 (d, 3 H, \(J=6.6\ \mathrm{Hz}\))

Figure 5

9.5 Provide the structures for products K and L. Indicate how the products are related.

(a) Epimers  (b) Enantiomers

(c) Diastereomers  (d) Constitutional Isomers

The choice of the electrode material can influence the selectivity of an organic electrosynthetic reaction. The reductive electrolysis of benzaldehyde (M) (16 mM in 1 M aqueous \(\ce{KOH}\), \(\ce{Pt}\) anode, −1.3 V vs. \(\ce{Ag/AgCl}\)) yields different products depending on the cathode material used. Strong binding to the surface favors intermolecular reactions. The figure below shows the product distribution for different cathode materials and the mass spectra of the products.

Figure 6

9.6 Provide the structure of N and O.

Alkenes, such as enol ethers, can be oxidatively coupled. This typically involves the anodic oxidation of the alkene fragment to yield a radical cation which can be intercepted by a nucleophile.

9.7 Provide the structural formulae of P, Q, R, and S in the scheme below. Indicating stereochemistry is not required. Hint: S is a tricyclic product.

Figure 7

Official English text of the problem.

Answers

  • 9.1
Label Identity and structural formula SMILES
A Octadecane, \(\ce{CH3(CH2)16CH3}\) CCCCCCCCCCCCCCCCCC
B Carbon dioxide, \(\ce{O=C=O}\) O=C=O
C Hydrogen, \(\ce{H-H}\) [H][H]
  • 9.2

Oxidation: \[ \ce{2C9H19COO- -> C18H38 + 2CO2 + 2e-} \]

Reduction: \[ \ce{2CH3OH + 2e- -> H2 + 2CH3O-} \]

Overall: \[ \boxed{\ce{2C9H19COO- + 2CH3OH -> C18H38 + 2CO2 + H2 + 2CH3O-}} \]

  • 9.3
Intermediate Identity SMILES
1 Decanoyloxy radical, \(\ce{C8H17CH2C(=O)O^{\bullet}}\) CCCCCCCCCC(=O)[O]
2 Nonan-1-yl radical, \(\ce{C8H17CH2^{\bullet}}\) CCCCCCCC[CH2]
  • 9.4
Label Identity SMILES
D Phenylacetic acid O=C(O)Cc1ccccc1
E Benzyl radical [CH2]c1ccccc1
F Benzyl cation [CH2+]c1ccccc1
G Benzyl phenylacetate O=C(Cc1ccccc1)OCc1ccccc1
H Benzyl methyl ether, also called methoxymethylbenzene COCc1ccccc1
  • 9.5

K and L are the two diastereomeric forms of ethyl 2-(oxolan-3-yl)propanoate, each obtained as a racemate:

Diastereomeric form Configurations: propanoate C2, oxolane C3 SMILES of its two enantiomers
First racemate \((2R,3R)\) and \((2S,3S)\) CCOC(=O)[C@H](C)[C@H]1CCOC1 and CCOC(=O)[C@@H](C)[C@@H]1CCOC1
Second racemate \((2S,3R)\) and \((2R,3S)\) CCOC(=O)[C@@H](C)[C@H]1CCOC1 and CCOC(=O)[C@H](C)[C@@H]1CCOC1

The relationship is (c) diastereomers, more specifically (a) epimers when representatives with the same oxolane configuration are compared. The supplied shifts do not establish which racemate is K and which is L.

  • 9.6
Label Identity SMILES
N Benzyl alcohol, \(\ce{C7H8O}\) OCc1ccccc1
O Hydrobenzoin, or 1,2-diphenylethane-1,2-diol, \(\ce{C14H14O2}\) OC(c1ccccc1)C(O)c1ccccc1

The stereochemistry of O is not determined by the supplied mass spectrum.

  • 9.7

P: The tris(isopropoxy)silyl ketene N,O-acetal of the starting imide; its side-chain carbonyl becomes \(\ce{N-C(OSi(OiPr)3)=CH-}\).
SMILES: CC(C)O[Si](OC(C)C)(OC(C)C)OC(=CC(C)CCc1cocc1C)N1C(c2ccccc2)COC1=O

Q: 3-(3,6-Dimethyl-4,5,6,7-tetrahydrobenzofuran-7-carbonyl)-4-phenyl-1,3-oxazolidin-2-one.
SMILES: CC1CCc2c(C)coc2C1C(=O)N1C(c2ccccc2)COC1=O

R: (3,6-Dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)methanol.
SMILES: CC1CCc2c(C)coc2C1CO

S, proposed formula-consistent assignment: A methoxy-substituted fused tricyclic ketone, describable as 3-methoxy-4,8-dimethyl-2-oxatricyclo[7.4.0.0\(^{1,5}\)]tridec-4-en-12-one.
SMILES: CC1CCC2=C(C)C(OC)OC23C1CCC(=O)C3

S contains fused six-, six-, and five-membered rings.

Solution

Common species used in the equations are methanol CO, methoxide C[O-], water O, hydroxide [OH-], and the proton [H+]. Radical electrons in the radical SMILES are represented by the bracketed atoms’ incomplete valence.

9.1 — Kolbe products

The starting acid is decanoic acid, CCCCCCCCCC(=O)O. Removing its carboxyl carbon as carbon dioxide leaves a nine-carbon fragment. Coupling two such fragments therefore gives the eighteen-carbon alkane:

\[ \ce{2C8H17CH2^{\bullet} -> C8H17CH2CH2C8H17}. \]

Thus A is octadecane.

The gas B is carbon dioxide. It reacts with calcium hydroxide, [Ca+2].[OH-].[OH-], to precipitate calcium carbonate, [Ca+2].[O-]C(=O)[O-]:

\[ \ce{CO2 + Ca(OH)2 -> CaCO3(s) + H2O}. \]

The flammable gas C is hydrogen, produced at the cathode.

9.2 — Half-reactions and overall reaction

The reacting anion is decanoate, CCCCCCCCCC(=O)[O-]. Each decanoate loses one electron and one molecule of carbon dioxide. Two resulting radicals combine, so formation of one molecule of octadecane releases two electrons:

\[ \ce{2C9H19COO- -> C18H38 + 2CO2 + 2e-}. \]

Methanol supplies the hydrogen evolved at the cathode:

\[ \ce{2CH3OH + 2e- -> H2 + 2CH3O-}. \]

Adding these equations gives the overall ionic equation stated in the answers. Both sides have charge \(-2\), and all atoms balance.

Methoxide also deprotonates the starting acid:

\[ \ce{C9H19COOH + CH3O- -> C9H19COO- + CH3OH}. \]

Adding two copies of this acid–base reaction to the electrolysis equation gives the formal net equation written from the neutral acid:

\[ \boxed{\ce{2C9H19COOH -> C18H38 + 2CO2 + H2}}. \]

This net equation does not remove the mechanistic requirement that the acid first be deprotonated.

9.3 — Radical intermediates

Anodic one-electron oxidation gives the neutral carboxyl radical 1:

\[ \ce{C9H19COO- -> C9H19CO2^{\bullet} + e-}. \]

In a structural drawing, the unpaired electron is placed on the singly bonded oxygen of the carboxyl group.

Decarboxylation then gives the primary carbon radical 2:

\[ \ce{C9H19CO2^{\bullet} -> C9H19^{\bullet} + CO2}. \]

Two nonan-1-yl radicals form a carbon–carbon bond by pairing their unpaired electrons:

\[ \ce{2C9H19^{\bullet} -> C18H38}. \]

9.4 — Benzylic overoxidation

The dimer drawn in the scheme is bibenzyl, or 1,2-diphenylethane, c1ccccc1CCc2ccccc2. Cutting its central carbon–carbon bond identifies the two precursor radicals as benzyl radicals. The acid that loses carbon dioxide to generate a benzyl radical must therefore be phenylacetic acid, D.

Its conjugate base is phenylacetate, O=C([O-])Cc1ccccc1:

\[ \ce{C6H5CH2COO- -> C6H5CH2^{\bullet} + CO2 + e-}. \]

The benzyl radical E can lose another electron:

\[ \ce{C6H5CH2^{\bullet} -> C6H5CH2+ + e-}. \]

This produces F, a resonance-stabilized benzyl cation. Stabilization of this cation makes overoxidation more accessible than for the primary alkyl radical in the first example.

Capture by phenylacetate gives ester G:

\[ \ce{C6H5CH2+ + C6H5CH2COO- -> C6H5CH2C(=O)OCH2C6H5}. \]

Capture by methanol, followed by loss of a proton, gives ether H:

\[ \ce{C6H5CH2+ + CH3OH -> C6H5CH2OCH3 + H+}. \]

9.5 — Radical cyclization and stereochemistry

The starting compounds are:

  • I: ethyl \((2E)\)-4-(2-carboxyethoxy)but-2-enoate, CCOC(=O)/C=C/COCCC(=O)O.
  • J: acetic acid, CC(=O)O.

Decarboxylation of I generates the terminal primary radical represented by CCOC(=O)/C=C/COC[CH2]. This radical undergoes a 5-exo-trig cyclization: the radical-bearing carbon bonds to the alkene carbon nearer the ether tether.

The resulting five-membered ring contains one oxygen and four carbons. The remaining radical is on the carbon adjacent to the ester carbonyl, where it is stabilized. This intermediate is the α-radical of ethyl 2-(oxolan-3-yl)acetate, CCOC(=O)[CH]C1CCOC1.

Acetate produces methyl radicals, [CH3], by oxidative decarboxylation. Coupling a methyl radical with the ester-stabilized radical gives

\[ \ce{EtO2C-CH(CH3)-(oxolan-3-yl)}, \]

namely ethyl 2-(oxolan-3-yl)propanoate.

The proton inventory supports this structure:

Feature Expected protons per molecule Corresponding observations
Ester ethoxy group 2 H in \(\ce{OCH2}\), 3 H in \(\ce{CH3}\) 4.18–4.08 ppm; methyl triplet
Two ring methylene groups adjacent to oxygen 4 H 3.95–3.60 and 3.43 ppm
Two methine groups 2 H 2.55–2.25 ppm
Remaining ring methylene group 2 H 2.20–1.95 and 1.65–1.50 ppm
Methyl attached to a methine 3 H Methyl doublet

The shared integrals printed for the mixture are twice these per-molecule values. Each product therefore has sixteen hydrogens, consistent with \(\ce{C9H16O3}\).

Two stereogenic centres are formed: oxolane C3 and propanoate C2. With achiral starting materials and conditions, the products occur as two racemic pairs:

\[ (R,R)/(S,S) \qquad\text{and}\qquad (S,R)/(R,S). \]

The two pairs are diastereomeric. Comparing, for example, the \((R,R)\) and \((S,R)\) representatives shows that they differ at only the propanoate stereocentre; they are therefore also epimers.

The small chemical-shift differences distinguish the diastereomeric products but do not assign their configurations.

9.6 — Carbonyl reduction versus reductive coupling

Benzaldehyde M, O=Cc1ccccc1, has formula \(\ce{C7H6O}\).

The molecular-ion peak at \(m/z=108\) corresponds to benzyl alcohol, N, with formula \(\ce{C7H8O}\). Its formation is the ordinary two-electron reduction of an aldehyde:

\[ \ce{C6H5CHO + 2H2O + 2e- -> C6H5CH2OH + 2OH-}. \]

The molecular-ion peak at \(m/z=214\) corresponds to hydrobenzoin, O, with formula \(\ce{C14H14O2}\). Its nominal molecular mass is that of two benzaldehyde molecules plus two hydrogen atoms:

\[ 2(106)+2=214\ \mathrm{Da}. \]

It results from reductive coupling of two carbonyl groups:

\[ \ce{2C6H5CHO + 2H2O + 2e- -> C6H5CH(OH)CH(OH)C6H5 + 2OH-}. \]

Mechanistically, one-electron reduction produces ketyl-type intermediates, which couple through their carbonyl carbons before protonation gives the diol.

The distribution is consistent with the stated surface effect: cathodes favouring intermolecular coupling give more O, whereas platinum predominantly gives N. Mass spectra alone do not distinguish meso-hydrobenzoin from its other stereoisomeric forms.

9.7 — Enol formation, annulation, reduction, and the final cyclization

The starting imide is 3-[3-methyl-5-(4-methylfuran-3-yl)pentanoyl]-4-phenyl-1,3-oxazolidin-2-one, CC(CCc1cocc1C)CC(=O)N1C(c2ccccc2)COC1=O.

Formation of P. Base removes a proton α to the external acyl carbonyl, and silylation traps the enolate on oxygen. The relevant transformation is

\[ \ce{-N-C(=O)-CH2-CH(CH3)-} \quad\longrightarrow\quad \ce{-N-C(OSi(OiPr)3)=CH-CH(CH3)-}. \]

The silicon substituents are isopropoxy groups, not isopropyl groups. Introducing \(\ce{Si(OiPr)3}\) while replacing one hydrogen changes the starting formula by \(\ce{C9H20O3Si}\):

\[ \ce{C20H23NO4} \quad\longrightarrow\quad \ce{C29H43NO7Si}. \]

This matches the formula printed for P.

Formation of Q. Anodic oxidation activates the enol double bond. The neighbouring, initially unsubstituted furan α-carbon attacks the former carbonyl α-carbon, closing a six-membered ring.

The new ring follows this sequence:

\[ \text{former carbonyl α-carbon} -\ce{CH(CH3)} -\ce{CH2} -\ce{CH2} -\text{tether-bearing furan carbon} -\text{attacking furan α-carbon}. \]

Further oxidation/proton loss and the acidic work-up restore the furan π-system and the external carbonyl. Relative to the starting imide, a new carbon–carbon bond replaces two carbon–hydrogen bonds. Consequently, Q has formula \(\ce{C20H21NO4}\), two hydrogens fewer than the starting material.

Its bicyclic portion is a 3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran with the auxiliary-bearing carbonyl substituent at C7.

Formation of R. Hydride reduction cleaves the external N-acyl group from the oxazolidinone auxiliary and converts that acyl carbon into a primary alcohol. Thus the substituent at benzofuran C7 becomes \(\ce{-CH2OH}\), giving R, \(\ce{C11H16O2}\).

The following steps independently confirm this assignment. They transform that substituent successively as follows:

\[ \ce{-CH2OH} \;\longrightarrow\; \ce{-CHO} \;\longrightarrow\; \ce{-CH=CHCO2Me} \;\longrightarrow\; \ce{-CH2CH2CO2Me}. \]

These changes are alcohol oxidation, Horner–Wadsworth–Emmons olefination, and alkene reduction.

The resulting methyl ester is methyl 3-(3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran-7-yl)propanoate, CC1CCc2c(C)coc2C1CCC(=O)OC.

Methylenation converts its ester carbonyl into the drawn enol ether:

\[ \ce{-CH2CH2C(=O)OMe} \quad\longrightarrow\quad \ce{-CH2CH2C(OMe)=CH2}. \]

This compound is 7-(3-methoxybut-3-en-1-yl)-3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran, CC1CCc2c(C)coc2C1CCC(=C)OC. Its drawn structure has formula \(\ce{C15H22O2}\), not the printed \(\ce{C15H22O3}\).

Proposed formation of S. Number the bicyclic starting material as a benzofuran: the oxygen is position 1; the methyl-substituted furan carbon is C3; the fused carbons are C3a and C7a; and the side chain is attached at C7.

The formula-consistent annulation is described precisely by these changes:

  1. Form a bond between the terminal enol-ether methylene carbon and furan C7a. This closes another six-membered ring.
  2. C7a becomes saturated and bears no hydrogen. The remaining furan-derived double bond lies between C3 and C3a.
  3. Methanol captures the furan-derived oxocarbenium centre at C2, installing a methoxy group there.
  4. Convert the original side-chain enol-ether carbon into a ketone.

The new six-membered ring is therefore

\[ \text{C7}-\ce{CH2}-\ce{CH2}-\ce{C(=O)}-\ce{CH2}-\text{C7a}. \]

Together with the original six-membered ring and the now nonaromatic five-membered oxygen heterocycle, this gives the proposed tricyclic S.

The assigned SMILES has formula \(\ce{C15H22O3}\). Its degree of unsaturation is

\[ \mathrm{DBE}=\frac{2(15)+2-22}{2}=5, \]

accounted for by three rings, one carbon–carbon double bond, and one carbonyl double bond. This agrees with both the stated formula and the tricyclic hint.

The answers were checked against the official answers published by the organisers.