IChO 2025 · Theory problem 1

Isocaryophyllene, clovene, and humulene

Download PDFIChO 2025

6% of the total

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 Total
7 3 6 2 2 8 2 2 2 34
Figure 1

Sesquiterpenes have the formula \(\ce{C15H24}\). They are secondary metabolites in plants and both deter insects which eat plants and attract animals which eat the insects.

Isocaryophyllene (i-Cy) is a sesquiterpene found in oregano, rosemary, pepper, and cloves.

The structural formula of i-Cy can be determined by performing various reactions and analysing the products as shown in the figure.

Figure 2

equiv. = translation 'equiv.'

1.1 Draw the structures of i-Cy, A, and B. Stereochemistry is not required.

1.2 Circle the stereocentres in compound C and assign them as \(R\) or \(S\).

Clovene (Cv) can be synthesised from i-Cy under acid catalysis. The synthesis of Cv starts from compound D.

Figure 3

\(\ce{H+}\) (cat.)="translation \(\ce{H+}\) (cat.)"

1.3 Draw the structures of compounds E and F. Stereochemistry is not required.

For steps '1' and '2' several reagents could be considered. For example:

  • ☐ PCC
  • ☐ \(\ce{K2Cr2O7, H2SO4, H2O}\)
  • ☐ \(\ce{MnO2}\)
  • ☐ (i) \(\ce{OsO4}\), (ii) \(\ce{KHSO3}\)
Figure 4

1.4 From the reagents above, tick which one(s) would be suitable for step '1'.

1.5 From the reagents above, tick which one(s) would be suitable for step '2'.

The final part of the synthesis is shown.

Figure 5

1.6 Draw the structures of compounds I, J, and K. Stereochemistry is not required.

Humulene (Hu) is another sesquiterpene. It can be converted to α-caryophyllene alcohol (α-Ca), which is similar in structure to Cv. This conversion is an acid-catalysed hydration reaction which takes place via multiple intermediate structures. Incomplete structures of some intermediates, X and Y, are shown.

Figure 6

\(\ce{H+}\) (cat.)="translation \(\ce{H+}\) (cat.)"

The transformation from Hu to X is an acid-catalysed isomerisation reaction. Intermediate Y is charged.

1.7 Complete the structure of intermediate X by adding double bonds in the correct places.

1.8 Complete the structure of intermediate Y by adding a positive charge in the correct place.

Five carbon atoms are circled in Hu. Through understanding the mechanism we can determine where these five carbon atoms end up in α-Ca.

Figure 7

1.9 Circle the five corresponding carbon atoms in α-Ca which are circled in Hu.

Official English text of the problem.

Answers

  • 1.1

i-Cy — isocaryophyllene, 4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene:
CC1=CCCC(=C)C2CC(C)(C)C2CC1

A — 8-(hydroxymethyl)-4,11,11-trimethylbicyclo[7.2.0]undec-4-ene:
CC1=CCCC(CO)C2CC(C)(C)C2CC1

B — tetrahydroisocaryophyllene, 2,6,10,10-tetramethylbicyclo[7.2.0]undecane:
CC1CCCC(C)C2CC(C)(C)C2CC1

  • 1.2 Circle the three consecutive stereocentres running from left to right across the lower edge of the cyclobutane and into the side chain. Their configurations are \(R,\ S,\ R\).

C — (4R)-5-hydroxy-4-[(1S,2R)-3,3-dimethyl-2-(3-oxobutyl)cyclobutyl]pentanal:
CC(=O)CC[C@H]1C(C)(C)C[C@@H]1[C@H](CO)CCC=O

  • 1.3

E — the five-membered lactone of 2-(2-hydroxy-5-methylbicyclo[3.3.1]non-3-en-1-yl)acetic acid:
O=C1CC23C(O1)C=CC(C)(CCC2)C3

F — 1-(2-hydroxyethyl)-5-methylbicyclo[3.3.1]non-3-en-2-ol:
OCCC12C(O)C=CC(C)(CCC1)C2

  • 1.4 Tick \(\ce{MnO2}\) only — manganese(IV) oxide, formal ionic SMILES [Mn+4].[O-2].[O-2]. This represents its composition; the solid has an extended lattice.

  • 1.5 Tick \(\ce{K2Cr2O7, H2SO4, H2O}\) only:

Potassium dichromate [K+].[K+].[O-][Cr](=O)(=O)O[Cr](=O)(=O)[O-]; sulfuric acid OS(=O)(=O)O; water O.

  • 1.6

I — methyl 2-(5-methyl-2-oxobicyclo[3.3.1]nonan-1-yl)acetate:
COC(=O)CC12C(=O)CCC(C)(CCC1)C2

J — the ethylene ketal of 2-(5-methyl-2-oxobicyclo[3.3.1]nonan-1-yl)acetic acid:
O=C(O)CC12C3(OCCO3)CCC(C)(CCC1)C2

Under the stated alkaline hydrolysis conditions, J is present as its carboxylate; its sodium salt is:
[Na+].O=C([O-])CC12C3(OCCO3)CCC(C)(CCC1)C2

K — 5-methyl-1-(2-oxobutyl)bicyclo[3.3.1]nonan-2-one:
CCC(=O)CC12C(=O)CCC(C)(CCC1)C2

  • 1.7 X — (1Z,3E,7E)-1,5,5,8-tetramethylcycloundeca-1,3,7-triene:
    CC1(C)/C=C/C=C(C)\CCC/C(C)=C/C1

In the supplied X drawing, add double bonds to:

  1. The upper-right sloping bond, one bond beyond the gem-dimethyl carbon.
  2. The right-hand vertical bond ending at the methyl-bearing carbon.
  3. The bond from the left methyl-bearing carbon to the next carbon above and to its right.
  • 1.8 Put \(+\) on the lower-right methyl-bearing carbon of the six-membered ring.

Y — the tricyclic tertiary cyclobutylcarbinyl carbocation:
CC1(C)CC2C3[C+](C)CCCC3(C)C2C1

  • 1.9 In α-caryophyllene alcohol, circle:
  1. Both carbons forming the bottom edge of the top five-membered ring.
  2. Both methyl-bearing bridgeheads, on the left and right.
  3. The central bridge carbon bearing \(\ce{OH}\).

α-Caryophyllene alcohol:
CC1(C)CC2C(C1)C1(C)CCCC2(C)C1O

Solution

1.1 — Reconstructing i-Cy, A, and B

The degree of unsaturation of \(\ce{C15H24}\) is

\[ \mathrm{DBE}=\frac{2(15)+2-24}{2}=4. \]

Hydrogenation gives \(\ce{C15H28}\), whose DBE is 2. Thus hydrogenation removes two units of unsaturation. The ozonolysis products identify these as two carbon–carbon double bonds, leaving two rings.

The hydrogenation balance is

\[ \ce{C15H24 + 2H2 -> C15H28}. \]

Thus the uptake is \(2\ \mathrm{mol}\) of hydrogen per mole of i-Cy.

The ozonolysis products determine how to reconnect the carbon skeleton:

  • Methanal, C=O, identifies a terminal \(\ce{=CH2}\) group.
  • Its former double-bond partner is the carbonyl carbon directly attached to the cyclobutane.
  • The remaining aldehyde and methyl ketone must be reconnected by a double bond. This closes a nine-membered ring sharing one bond with the cyclobutane.

The supplied larger ozonolysis product is 4-[(1S,2R)-3,3-dimethyl-2-(3-oxobutyl)cyclobutyl]-4-oxobutanal:

CC(=O)CC[C@H]1C(C)(C)C[C@@H]1C(=O)CCC=O

Its formula is \(\ce{C14H22O3}\). An atom-balanced representation of the reductive ozonolysis is

\[ \ce{C15H24 + 2O3 + 2Zn + 4CH3COOH -> C14H22O3 + CH2O + 2Zn(CH3COO)2 + 2H2O}. \]

This gives the i-Cy structure listed in the answers: a fused four-/nine-membered bicyclic system containing one internal alkene and one exocyclic methylene.

Borane, [BH3], preferentially hydroborates the less hindered exocyclic double bond. Anti-Markovnikov addition places boron on the terminal carbon; oxidation with hydrogen peroxide, OO, replaces the carbon–boron bond with a carbon–oxygen bond. Consequently,

\[ \ce{>C=CH2 -> >CH-CH2OH}. \]

The internal alkene remains intact. Each borane molecule contains three B–H bonds, so \(1/3\) equivalent supplies enough B–H bonds to hydroborate one double bond per substrate molecule. Using boric acid, OB(O)O, for neutral-work-up bookkeeping,

\[ \ce{3C15H24 + BH3 + 3H2O2 -> 3C15H26O + B(OH)3}. \]

This identifies A. Its remaining internal double bond undergoes ozonolysis to give C:

\[ \ce{C15H26O + O3 + Zn + 2CH3COOH -> C15H26O3 + Zn(CH3COO)2 + H2O}. \]

Complete hydrogenation of both double bonds instead gives B: the exocyclic methylene becomes a methyl group, and the internal double bond becomes a single bond.

1.2 — Absolute configurations in C

Label the three stereocentres from left to right in the supplied drawing as \(L\), \(M\), and \(R\).

Centre CIP priorities, highest to lowest Assignment
\(L\): left lower cyclobutane carbon Gem-dimethyl ring carbon \(>\) \(M\) \(>\) methyl-ketone side chain \(>\) H \(R\)
\(M\): right lower cyclobutane carbon \(R\) \(>\) \(L\) \(>\) ring methylene \(>\) H \(S\)
\(R\): adjacent side-chain carbon \(\ce{CH2OH}\) \(>\) \(M\) \(>\) \(\ce{CH2CH2CHO}\) \(>\) H \(R\)

At \(L\), the three carbon ligands initially give the comparison lists

\[ [C,C,C] > [C,C,H] > [C,H,H]. \]

Its hydrogen points away, so the clockwise \(1\to2\to3\) sequence gives \(R\).

At \(M\), the two leading ligands initially tie. The right-hand ligand wins at the next comparison because its hydroxymethyl branch reaches oxygen. Hydrogen points towards the observer, so the apparent sense must be reversed, giving \(S\).

At \(R\), the hydroxymethyl carbon has the comparison list \([O,H,H]\), which outranks both carbon-only alternatives. Reversing the apparent sense because hydrogen points towards the observer gives \(R\).

Therefore the required assignments are

\[ \boxed{R,\ S,\ R\quad\text{from left to right}.} \]

The gem-dimethyl carbon is not stereogenic because its two methyl substituents are identical.

1.3 — Lactonization and reduction

D is methyl 2-(2-hydroxy-5-methylbicyclo[3.3.1]non-3-en-1-yl)acetate:

COC(=O)CC12C(O)C=CC(C)(CCC1)C2

Its allylic hydroxyl group is positioned to attack the ester intramolecularly. Acid catalysis activates the ester carbonyl, and loss of methanol, CO, produces a five-membered lactone.

The new lactone ring follows the sequence

\[ \text{alcohol-bearing carbon} -\ce{O} -\ce{C(=O)} -\ce{CH2} -\text{adjacent bridgehead}. \]

The formula balance is

\[ \ce{C13H20O3 -> C12H16O2 + CH3OH}, \]

which agrees exactly with the stated formula of E.

Lithium aluminium hydride, [Li+].[AlH4-], reduces the lactone carbonyl and opens its acyl–oxygen bond. After work-up:

  • The original alcohol oxygen becomes the secondary allylic hydroxyl group again.
  • The former ester carbonyl carbon becomes the terminal carbon of a \(\ce{-CH2CH2OH}\) substituent.
  • The carbon–carbon double bond remains intact.

Thus F is the diol specified in the answers, with formula \(\ce{C12H20O2}\). A balanced reduction/work-up equation, omitting spectator lithium ions, is

\[ \ce{2C12H16O2 + AlH4^- + 4H+ -> 2C12H20O2 + Al^{3+}}. \]

1.4 — Selective oxidation of F to G

G is 1-(2-hydroxyethyl)-5-methylbicyclo[3.3.1]non-3-en-2-one:

OCCC12C(=O)C=CC(C)(CCC1)C2

The required transformation oxidizes the secondary allylic alcohol while preserving the non-allylic primary alcohol.

Manganese(IV) oxide performs this selective oxidation. In oxygen-equivalent notation, where \(\ce{[O]}\) denotes one formal oxygen-atom oxidizing equivalent,

\[ \ce{C12H20O2 + [O] -> C12H18O2 + H2O}. \]

The other choices are unsuitable:

  • PCC would also oxidize the primary alcohol to an aldehyde.
  • Acidified dichromate would also oxidize the primary alcohol, ultimately to a carboxylic acid.
  • Osmium tetroxide followed by bisulfite work-up would dihydroxylate the alkene.

Therefore, tick \(\ce{MnO2}\) only.

1.5 — Oxidation of G to H

H is 2-(5-methyl-2-oxobicyclo[3.3.1]non-3-en-1-yl)acetic acid:

O=C(O)CC12C(=O)C=CC(C)(CCC1)C2

The primary alcohol must undergo the four-electron oxidation

\[ \ce{-CH2OH -> -COOH}. \]

Aqueous acidified dichromate gives this conversion. The balanced ionic equation is

\[ \ce{3C12H18O2 + 2Cr2O7^{2-} + 16H+ -> 3C12H16O3 + 4Cr^{3+} + 11H2O}. \]

PCC normally stops at the aldehyde under its standard anhydrous conditions. Manganese dioxide does not provide the required oxidation of this non-allylic primary alcohol, and osmium tetroxide targets the alkene.

Therefore, tick \(\ce{K2Cr2O7, H2SO4, H2O}\) only.

1.6 — Identifying I, J, and K

For clarity, number the bicyclo[3.3.1]nonane framework so that the side-chain-bearing bridgehead is C1, the adjacent ketone carbon is C2, and the methyl-bearing opposite bridgehead is C5.

Formation of I. Hydrogenation removes the alkene in H while retaining the ketone. Methanol under acid catalysis then esterifies the carboxylic acid.

The overall organic balance is

\[ \ce{C12H16O3 + H2 + CH3OH -> C13H20O3 + H2O}. \]

Thus I contains the saturated bicyclic ketone and a \(\ce{-CH2COOCH3}\) substituent at C1.

Formation of J. Ethylene glycol, ethane-1,2-diol OCCO, protects the ring ketone as a five-membered cyclic ketal. Aqueous sodium hydroxide subsequently hydrolyses the methyl ester without removing this ketal.

The combined balance under the stated alkaline conditions is

\[ \ce{C13H20O3 + HOCH2CH2OH + OH^- -> C14H21O4^- + CH3OH + H2O}. \]

Acidification would give the neutral acid shown in the principal answer:

\[ \ce{C14H21O4^- + H+ -> C14H22O4}. \]

Therefore J retains the ethylene ketal at C2 and has a \(\ce{-CH2COOH}\) group, or its carboxylate, at C1.

Formation of K. Thionyl chloride converts the carboxylic acid group into an acyl chloride. Lithium diethylcuprate then replaces the acyl chloride’s chlorine with one ethyl group, producing a ketone.

Writing \(R\) for the ketal-protected remainder of J and \(\mathrm{Et}=\ce{C2H5}\),

\[ \ce{RCOOH + SOCl2 -> RCOCl + SO2 + HCl}, \]

\[ \ce{RCOCl + LiCuEt2 -> RCOEt + EtCu + LiCl}. \]

The corresponding protected structures are:

Intermediate SMILES
Ketal-protected acyl chloride derived from J O=C(Cl)CC12C3(OCCO3)CCC(C)(CCC1)C2
Ethylene-ketal-protected K CCC(=O)CC12C3(OCCO3)CCC(C)(CCC1)C2

Finally, aqueous acid hydrolyses the ketal and restores the original ring ketone:

\[ \ce{C16H26O3 + H2O -> C14H22O2 + HOCH2CH2OH}. \]

Hence K contains two ketones: the ring ketone and the side chain

\[ \ce{-CH2-C(=O)-CH2-CH3}. \]

The following aldol condensation independently confirms this identification. The enolate formed on the ethyl side of the side-chain ketone attacks the ring ketone, closing a five-membered ring. Dehydration gives the depicted tricyclic enone:

CC1=C2CCC3(C)CCCC2(CC1=O)C3

Its formula balance is

\[ \ce{C14H22O2 -> C14H20O + H2O}. \]

The ethyl group’s terminal methyl consequently becomes the methyl substituent on the new enone double bond.

1.7 — Double bonds in X

Use the following atom-tracking labels, which are independent of systematic nomenclature:

  • Label the gem-dimethyl ring carbon of Hu C1.
  • Proceed clockwise around the Hu drawing to label the other ring atoms C2–C11.
  • The other methyl-bearing ring carbons are C5 and C9.

Humulene is (1E,4E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene. Its atom-mapped SMILES under this tracking convention is:

C[C:1]1(C)/[CH:2]=[CH:3]/[CH2:4]/[C:5](C)=[CH:6]/[CH2:7][CH2:8]/[C:9](C)=[CH:10]/[CH2:11]1

Its double bonds are therefore

\[ \mathrm{C2=C3,\qquad C5=C6,\qquad C9=C10}. \]

Acid-catalysed isomerization moves the C5=C6 bond to C4=C5:

  1. Protonation at C6 gives a carbocation at C5.
  2. Loss of a proton from C4 regenerates the acid catalyst and forms C4=C5.

The resulting conjugated diene enables the subsequent cyclization. Thus X has

\[ \boxed{\mathrm{C2=C3,\qquad C4=C5,\qquad C9=C10}.} \]

No atoms are gained or lost: Hu and X both have formula \(\ce{C15H24}\). In the supplied X drawing, C4=C5 has \(Z\) geometry, while the other two double bonds have \(E\) geometry; these geometries are included in the answer SMILES.

1.8 — Positive charge in Y

Starting from X, the cyclization can be followed by three electron-flow steps:

  1. Protonation at C2 of C2=C3 leaves a carbocation at C3.
  2. The C9=C10 π bond attacks through C10, forming the new C3–C10 bond and leaving a carbocation at C9.
  3. The C4=C5 π bond attacks through C4, forming the new C4–C9 bond and leaving a carbocation at C5.

These two new carbon–carbon bonds produce exactly the fused five-, four-, and six-membered rings drawn for Y.

The balance is

\[ \ce{C15H24 + H+ -> C15H25+}. \]

C5 is the lower-right methyl-bearing carbon in the six-membered ring. It has three carbon–carbon σ bonds, no attached hydrogen, and the positive charge.

1.9 — Tracking the five circled carbons

Under the numbering above, the five circled atoms in Hu are

\[ \boxed{\mathrm{C3,\ C4,\ C5,\ C9,\ C10}.} \]

The conversion of Y into α-caryophyllene alcohol involves a Wagner–Meerwein rearrangement:

  1. The C3–C4 σ bond migrates to the cationic C5, forming a new C3–C5 bond.
  2. The positive charge moves from C5 to C4.
  3. Water attacks C4, and deprotonation produces the alcohol.

This migration expands the four-membered ring and creates the bridged skeleton shown in the product. The hydroxyl-bearing carbon is therefore the original C4.

The hydration balance is

\[ \ce{C15H25+ + H2O -> C15H26O + H+}, \]

so the overall acid-catalysed reaction is

\[ \ce{C15H24 + H2O -> C15H26O}. \]

The atom-mapped SMILES of α-caryophyllene alcohol is:

C[C:1]1(C)[CH2:2][CH:3]2[CH:10]([CH2:11]1)[C:9]1(C)[CH2:8][CH2:7][CH2:6][C:5]2(C)[CH:4]1O

The required circles are therefore:

Original circled atom Position in the supplied α-Ca drawing
C3 Lower-right corner of the top five-membered ring
C10 Lower-left corner of the top five-membered ring
C9 Left methyl-bearing bridgehead
C5 Right methyl-bearing bridgehead
C4 Central bridge carbon bearing \(\ce{OH}\)

The mapped SMILES specifies atom identity and connectivity. The spatial arrangement of the bridges is conveyed by the supplied skeletal drawing; no additional absolute stereochemical assignment is requested in this part.

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