IChO 1985 · Theory problem 6

Synthesis of a sympathomimetic 2-phenylethylamine derivative from acetophenone

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The following scheme describes the synthesis of a compound D (with sympathomimetic effects) whose skeleton consists of 2-phenylethylamine.

Figure 1

Problems:

6.1 What reagents were used in steps a, b, c, and d?

6.2 Give the structural formulae of compounds B, C and D.

6.3 Is it possible to prepare 3-hydroxyacetophenone from the reaction between phenol, acetylchloride and \(\ce{AlCl3}\)? Give reasons for your answer.

6.4 Give the formulae of the compounds that are formed by the reaction of compound C with a) 10% \(\ce{HCl}\) and b) 10% \(\ce{NaOH}\).

6.5 By the asterisk denote the chirality centre in the formula of compound D.

6.6 Give the spatial formula of enantiomer (R) of compound D.

Official English text of the problem.

Answers

  • 6.1 a: Concentrated nitric acid O=[N+]([O-])O and concentrated sulfuric acid OS(=O)(=O)O. b: Iron [Fe] and hydrochloric acid Cl. c: Sodium nitrite [Na+].[O-]N=O and hydrochloric acid at \(0\text{–}5\,^\circ\mathrm{C}\), followed by warming with water O. d: Benzoyl chloride O=C(Cl)c1ccccc1 and sodium hydroxide [Na+].[OH-].

  • 6.2 B: 3-(2-Bromoacetyl)phenyl benzoate, O=C(CBr)c1cccc(OC(=O)c2ccccc2)c1, molecular formula \(\ce{C15H11BrO3}\). C: 2-Amino-1-(3-hydroxyphenyl)ethan-1-one, NCC(=O)c1cccc(O)c1, molecular formula \(\ce{C8H9NO2}\). D: 2-Amino-1-(3-hydroxyphenyl)ethan-1-ol (norphenylephrine), NCC(O)c1cccc(O)c1, molecular formula \(\ce{C8H11NO2}\).

  • 6.3 No. The phenolic hydroxyl group directs ring acetylation to the ortho and para positions; this route does not prepare the required meta isomer.

  • 6.4 a: C hydrochloride, [NH3+]CC(=O)c1cccc(O)c1.[Cl-], formula \(\ce{C8H10ClNO2}\). b: Sodium 3-(2-aminoacetyl)phenolate, NCC(=O)c1cccc([O-])c1.[Na+], formula \(\ce{C8H8NNaO2}\).

  • 6.5 The sole chirality centre is the benzylic alcohol carbon: \[ \ce{HO-C6H4-C^{*}H(OH)-CH2NH2} \] with meta substitution on the ring.

  • 6.6 (1R)-2-Amino-1-(3-hydroxyphenyl)ethan-1-ol: NC[C@H](O)c1cccc(O)c1. A Fischer projection has 3-hydroxyphenyl at the top, aminomethyl at the bottom, hydroxyl on the left, and hydrogen on the right.

Solution

In the condensed equations below, the two substituents on each \(\ce{C6H4}\) ring are meta, except where ortho or para is explicitly specified.

6.1 — Reagents and transformations

Step a: nitration. Acetophenone, CC(=O)c1ccccc1, is nitrated with concentrated nitric and sulfuric acids:

\[ \ce{C6H5COCH3 + HNO3 -> O2NC6H4COCH3 + H2O}. \]

The acetyl group withdraws electron density and is a deactivating, meta-directing substituent. The principal product is therefore 3-nitroacetophenone, CC(=O)c1cccc([N+](=O)[O-])c1.

Step b: reduction of the nitro group. Iron and hydrochloric acid reduce the nitro group to an amino group while preserving the ketone. In the acidic medium, the product is 3-aminoacetophenone hydrochloride, CC(=O)c1cccc([NH3+])c1.[Cl-]:

\[ \ce{O2NC6H4COCH3 + 3Fe + 7HCl -> [H3NC6H4COCH3]Cl + 3FeCl2 + 2H2O}. \]

The inorganic reduction product is iron(II) chloride, [Fe+2].[Cl-].[Cl-].

Step c: diazotization followed by hydrolysis. Sodium nitrite and hydrochloric acid at \(0\text{–}5\,^\circ\mathrm{C}\) convert the aromatic amino group into a diazonium group:

\[ \ce{[H3NC6H4COCH3]Cl + NaNO2 + HCl -> [N2C6H4COCH3]Cl + NaCl + 2H2O}. \]

The intermediate is 3-acetylbenzenediazonium chloride, CC(=O)c1cccc([N+]#N)c1.[Cl-]. Warming its aqueous solution replaces the diazonium group with hydroxyl:

\[ \ce{[N2C6H4COCH3]Cl + H2O -> HOC6H4COCH3 + N2 + HCl}. \]

This gives 3-hydroxyacetophenone, CC(=O)c1cccc(O)c1. The other products include sodium chloride, [Na+].[Cl-], and nitrogen, N#N.

Step d: protection by benzoylation. Benzoyl chloride and aqueous sodium hydroxide convert the phenolic hydroxyl group into a benzoate ester:

\[ \ce{HOC6H4COCH3 + C6H5COCl + NaOH -> C6H5COOC6H4COCH3 + NaCl + H2O}. \]

The product is 3-acetylphenyl benzoate, CC(=O)c1cccc(OC(=O)c2ccccc2)c1. Benzoylation protects the phenolic group and reduces its strong activation of the aromatic ring toward bromination.

6.2 — Identification of B, C and D

Formation of B. Bromine, BrBr, in acetic acid, CC(=O)O, brominates the ketone at its alpha carbon through the enol:

\[ \ce{C6H5COOC6H4COCH3 + Br2 -> C6H5COOC6H4COCH2Br + HBr}. \]

Thus B is the alpha-bromoketone 3-(2-bromoacetyl)phenyl benzoate. The coproduct is hydrogen bromide, present as hydrobromic acid, Br, in aqueous solution.

Formation of C. Hexamethylenetetramine, C1N2CN3CN1CN(C2)C3, effects a Delépine synthesis: a cage nitrogen displaces bromide from the bromomethyl group, and subsequent acidic hydrolysis releases a primary amine.

The aqueous acid treatment also hydrolyses the phenolic benzoate protecting group. This deprotection is required by the stated formula of C: the seven carbons of the benzoyl group are absent.

A balanced overall equation for the reaction with hexamethylenetetramine and the acidic hydrolysis is

\[ \begin{aligned} &\ce{C6H5COOC6H4COCH2Br + C6H12N4 + 3HBr + 7H2O}\\ &\qquad\ce{-> [HOC6H4COCH2NH3]Br + C6H5COOH + 3NH4Br + 6HCHO}. \end{aligned} \]

The organic salt is C hydrobromide, [NH3+]CC(=O)c1cccc(O)c1.[Br-]. The other hydrolysis products are benzoic acid, O=C(O)c1ccccc1, ammonium bromide, [NH4+].[Br-], and formaldehyde, C=O.

Neutralization releases C; using sodium hydroxide, the relevant equation is

\[ \ce{[HOC6H4COCH2NH3]Br + NaOH -> HOC6H4COCH2NH2 + NaBr + H2O}. \]

Here sodium bromide is [Na+].[Br-]. Consequently,

\[ \boxed{\ce{C = HOC6H4COCH2NH2}} \]

with molecular formula \(\ce{C8H9NO2}\), as given.

Formation of D. Catalytic hydrogenation with hydrogen, [H][H], reduces the ketone to a secondary alcohol:

\[ \ce{HOC6H4COCH2NH2 + H2 ->[catalyst] HOC6H4CH(OH)CH2NH2}. \]

Therefore,

\[ \boxed{\ce{D = HOC6H4CH(OH)CH2NH2}}. \]

The addition of two hydrogen atoms changes \(\ce{C8H9NO2}\) into \(\ce{C8H11NO2}\), matching the supplied formula. With an achiral catalyst, reduction of the planar carbonyl group gives a racemic mixture.

6.3 — Why direct acetylation of phenol does not give the required isomer

The proposed reagents are phenol, Oc1ccccc1, acetyl chloride, CC(=O)Cl, and aluminium chloride, Cl[Al](Cl)Cl.

The phenolic hydroxyl group directs electrophilic aromatic substitution to the ortho and para positions. Consequently, this reaction does not establish the meta relationship required for 3-hydroxyacetophenone.

O-Acetylation may occur first, giving phenyl acetate, CC(=O)Oc1ccccc1:

\[ \ce{C6H5OH + CH3COCl -> C6H5OCOCH3 + HCl}. \]

Aluminium chloride can promote a Fries rearrangement of this ester:

\[ \ce{C6H5OCOCH3 ->[AlCl3] HOC6H4COCH3} \qquad\text{(ortho or para product)}. \]

The resulting ring-acetylated products are 2-hydroxyacetophenone, CC(=O)c1ccccc1O, and/or 4-hydroxyacetophenone, CC(=O)c1ccc(O)cc1.

The supplied synthesis instead establishes the meta relationship by nitrating acetophenone, then converts the nitro substituent into hydroxyl.

6.4 — Reactions of C with acid and base

a) With 10% hydrochloric acid: the amino group is protonated, giving C hydrochloride:

\[ \ce{HOC6H4COCH2NH2 + HCl -> [HOC6H4COCH2NH3]+ + Cl-}. \]

Its structure is [NH3+]CC(=O)c1cccc(O)c1.[Cl-]; the phenolic group remains neutral.

b) With 10% sodium hydroxide: the phenolic hydroxyl group is deprotonated, giving sodium 3-(2-aminoacetyl)phenolate:

\[ \ce{HOC6H4COCH2NH2 + NaOH -> [OC6H4COCH2NH2]- + Na+ + H2O}. \]

Its structure is NCC(=O)c1cccc([O-])c1.[Na+]; the amino group remains neutral.

6.5 — Chirality centre

The carbon formed by reduction of the carbonyl group bears four different substituents:

  • hydroxyl;
  • hydrogen;
  • aminomethyl;
  • 3-hydroxyphenyl.

It is therefore the only chirality centre:

\[ \boxed{\ce{HO-C6H4-C^{*}H(OH)-CH2NH2}}. \]

Place the asterisk on the side-chain carbon directly bonded to the benzene ring and to the alcoholic hydroxyl group.

6.6 — Spatial formula of the \(R\) enantiomer

The Cahn–Ingold–Prelog priorities at the stereocentre are

\[ \underbrace{\ce{-OH}}_{1} > \underbrace{\ce{-CH2NH2}}_{2} > \underbrace{\ce{-C6H4OH}}_{3} > \underbrace{\ce{-H}}_{4}. \]

The two carbon-attached groups are distinguished at the next comparison: the aminomethyl carbon has the list \((\ce{N},\ce{H},\ce{H})\), whereas the aromatic carbon has \((\ce{C},\ce{C},\ce{C})\), including the aromatic multiple-bond duplication. Nitrogen outranks carbon, so aminomethyl has priority 2.

For a Fischer projection, place:

  • the 3-hydroxyphenyl group at the top;
  • the aminomethyl group at the bottom;
  • hydroxyl on the left;
  • hydrogen on the right.

The horizontal bonds point toward the observer, and the vertical bonds point away. The sequence \(1\rightarrow2\rightarrow3\) is counterclockwise on the page; because hydrogen points toward the observer, reversing that sense gives \(R\).

The corresponding stereochemical SMILES is NC[C@H](O)c1cccc(O)c1, representing (1R)-2-amino-1-(3-hydroxyphenyl)ethan-1-ol.

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