Question

Outline all steps in the synthesis from toluene of: (a) p-cresol via diazotizatiori; (b) p-cresol via thallation; (c) m-cresol via diazotizatiori; (d) m-cresol via thallation.

Short answer

(a) p-Cresol synthesis via diazotization: (1) Nitrate toluene with HNO3 and H2SO4; (2) Reduce nitro groups with Pd/C and H2; (3) Diazotize para-aminotoluene with NaNO2 and HCl; (4) React para-toluene-diazonium chloride with boiling H2O. (b) p-Cresol synthesis via thallation: (1) React toluene with Tl(OCOCF3)3; (2) Hydroxylate para-thallated toluene with NaOH. (c) m-Cresol synthesis via diazotization: (1) Nitrate toluene with HNO3 and H2SO4; (2) Reduce nitro groups with Pd/C and H2; (3) Diazotize ortho-aminotoluene with NaNO2 and HCl; (4) React ortho-toluene-diazonium chloride with boiling H2O. (d) m-Cresol synthesis via thallation: (1) React toluene with Tl(OCOCF3)3; (2) Hydroxylate ortho-thallated toluene with NaOH.

Step-by-step solution

1. Nitration of Toluene

First, nitrate the toluene by adding concentrated nitric acid (HNO3) and concentrated sulfuric acid (H2SO4) as a catalyst. This reaction produces a mixture of ortho-nitrotoluene and para-nitrotoluene. $\text{Toluene + HNO3 + H2SO4}\to \text{ortho-nitrotoluene + para-nitrotoluene}$

2. Reduction of Nitro Groups

Next, reduce the nitro groups in the ortho-nitrotoluene and para-nitrotoluene using palladium on carbon (Pd/C) and hydrogen gas (H2) as the reducing agent. This will convert the nitro groups to amino groups, forming ortho-aminotoluene and para-aminotoluene. $\text{ortho-nitrotoluene + H2}\to \text{ortho-aminotoluene}$ $\text{para-nitrotoluene + H2}\to \text{para-aminotoluene}$

3. Diazotization

Diazotize the para-aminotoluene by reacting it with sodium nitrite (NaNO2) and hydrochloric acid (HCl) in an ice-cold solution to form the diazonium salt, para-toluene-diazonium chloride. $\text{para-aminotoluene + NaNO2 + HCl}\to \text{para-toluene-diazonium chloride + NaCl}$

4. Formation of p-cresol

Finally, react the para-toluene-diazonium chloride with boiling water (H2O) to form p-cresol and nitrogen gas (N2). $\text{para-toluene-diazonium chloride + H2O}\to \text{p-cresol + N2 + HCl}$ ##Part (b): Synthesis of p-cresol from toluene via thallation##

1. Thallation of Toluene

First, react toluene with thallium(III) trifluoroacetate (Tl(OCOCF3)3) to form the para-thallated toluene. $\text{Toluene + Tl(OCOCF3)3}\to \text{para-thallated toluene + Tl(OCOCF3) }$

2. Hydroxylation

Next, hydroxylate the para-thallated toluene with a hydroxylating reagent, such as sodium hydroxide (NaOH), to form the p-cresol. $\text{para-thallated toluene + NaOH}\to \text{p-cresol + NaTl(OCOCF3) }$ ##Part (c): Synthesis of m-cresol from toluene via diazotization##

1. Nitration of Toluene

First, nitrate the toluene by adding concentrated nitric acid (HNO3) and concentrated sulfuric acid (H2SO4) as a catalyst. This reaction produces a mixture of ortho-nitrotoluene and para-nitrotoluene. $\text{Toluene + HNO3 + H2SO4}\to \text{ortho-nitrotoluene + para-nitrotoluene}$

2. Reduction of Nitro Groups

Next, reduce the nitro groups in the ortho-nitrotoluene and para-nitrotoluene using palladium on carbon (Pd/C) and hydrogen gas (H2) as the reducing agent. This will convert the nitro groups to amino groups, forming ortho-aminotoluene and para-aminotoluene. $\text{ortho-nitrotoluene + H2}\to \text{ortho-aminotoluene}$ $\text{para-nitrotoluene + H2}\to \text{para-aminotoluene}$

3. Diazotization

Diazotize the ortho-aminotoluene by reacting it with sodium nitrite (NaNO2) and hydrochloric acid (HCl) in an ice-cold solution to form the diazonium salt, ortho-toluene-diazonium chloride. $\text{ortho-aminotoluene + NaNO2 + HCl}\to \text{ortho-toluene-diazonium chloride + NaCl}$

4. Formation of m-cresol

Finally, react the ortho-toluene-diazonium chloride with boiling water (H2O) to form m-cresol and nitrogen gas (N2). $\text{ortho-toluene-diazonium chloride + H2O}\to \text{m-cresol + N2 + HCl}$ ##Part (d): Synthesis of m-cresol from toluene via thallation##

1. Thallation of Toluene

First, react toluene with thallium(III) trifluoroacetate (Tl(OCOCF3)3) to form the ortho-thallated toluene. $\text{Toluene + Tl(OCOCF3)3}\to \text{ortho-thallated toluene + Tl(OCOCF3) }$

2. Hydroxylation

Next, hydroxylate the ortho-thallated toluene with a hydroxylating reagent, such as sodium hydroxide (NaOH), to form the m-cresol. $\text{ortho-thallated toluene + NaOH}\to \text{m-cresol + NaTl(OCOCF3) }$

Key concepts

Toluene Nitration

Toluene nitration is a critical step in the synthesis of cresol derivatives. It involves the introduction of nitro groups into the toluene molecule, an aromatic hydrocarbon. This is achieved by treating toluene with concentrated nitric acid, using concentrated sulfuric acid as a catalyst. The sulfuric acid acts as a proton donor, enhancing the reactivity of the nitric acid, enabling it to add nitro groups to the toluene ring.
The nitration process typically yields a mixture of ortho-nitrotoluene and para-nitrotoluene. This is because the methyl group in toluene directs the incoming nitro group to the ortho and para positions on the aromatic ring. Nitration is exothermic, so controlling the temperature is essential to avert side reactions.

• Nitric acid is used to add nitro groups.
• Sulfuric acid acts as a catalyst.
• Produces ortho- and para-nitrotoluene.

Aromatic Diazotization

Aromatic diazotization is a fascinating chemical reaction where an amino group on an aromatic ring is converted into a diazonium salt. This is typically conducted in an ice-cold solution to prevent the reactive diazonium salt from decomposing immediately. In our example, para-aminotoluene is treated with a mixture of sodium nitrite and hydrochloric acid.
This reaction transforms the para-aminotoluene into para-toluene-diazonium chloride. The diazonium salt thus formed is highly versatile and can be used for further chemical transformations to produce a variety of aromatic compounds such as cresols by further reaction with water.

• Involves conversion of amino groups to diazonium salts.
• Performed in cold conditions to stabilize the salt.
• Useful for creating a wide range of aromatic compounds.

Thallation Reaction

Thallation is a unique and powerful approach to transform aromatic compounds with precision. In this process, toluene is reacted with thallium(III) trifluoroacetate. This reaction facilitates the introduction of thallium into the toluene molecule, specifically at the para or ortho position, depending on the reaction conditions.
The thallated intermediates are highly reactive and can be easily converted into other useful aromatic compounds through subsequent reactions. For instance, when reacting thallated toluene with a hydroxylating reagent like sodium hydroxide, it is transformed into cresols, an essential compound in various industries.

• Introduces thallium into the aromatic ring.
• Allows for selective modification of aromatic compounds.
• Followed by hydroxylation for further transformations.

Amino Group Reduction

Amino group reduction is an essential step in converting nitro compounds into amines. Through this process, nitro groups added during nitration are reduced to form amino groups. This is commonly achieved using hydrogen gas in the presence of a catalyst, like palladium on carbon (Pd/C).
This transformation is crucial in organic synthesis as it enables the nitrated toluene derivatives to react further, such as undergoing diazotization to form useful compounds like diazonium salts. Amines produced from this reduction serve as key intermediates in synthesizing various functionalized aromatic chemicals.

• Converts nitro groups to amino groups.
• Utilizes hydrogen and a catalyst for reduction.
• Vital for progressing to advanced synthetic steps.