Nitration of Acetophenone: Directing Effects of the Acetyl Group in EAS

3D Glass Rendering Of Chemical Compounds. [Audio] Nitration of Acetophenone: Directing Effects of the Acetyl Group in EAS Presented by Michael Nwachukwu Computational Chemistry Research STEC 4500 (Undergraduate Research Project) Spring 2025.

[Audio] Abstract This study examines the nitration of acetophenone, highlighting the meta-nitroacetophenone as the main product due to the electron-withdrawing effect of the carbonyl group. Both experimental and computational analyses confirm this selectivity, demonstrating the effectiveness of combining these approaches in optimizing organic synthesis..

[Audio] Introduction Acetophenone is a pivotal compound in organic chemistry, prized for its reactive benzene ring and carbonyl group. It acts as a crucial building block in the synthesis of pharmaceuticals, fragrances, and other fine chemicals. The nitration of acetophenone exemplifies electrophilic aromatic substitution (EAS), a fundamental reaction in organic chemistry. In this process, acetophenone reacts with a nitrating mixture (concentrated nitric and sulfuric acids) to yield nitroacetophenone. “Nitroacetophenone is an important intermediate in the field of organic synthesis and pharmaceutical synthesis, and is widely applied to o-nitroacetophenone, m-nitroacetophenone and p-nitroacetophenone. The o-nitroacetophenone is used for preparing a sensitizer and also used for preparing diabetes drugs such as linagliptin and the like; the m-nitroacetophenone can be prepared into m-aminoacetophenone through reduction, and the pharmaceutical industry is used for preparing epinephrine medicaments and the like; the p-nitroacetophenone is used for synthesizing broad-spectrum antibacterial antibiotic medicines such as chloramphenicol and synmycin, and is also used for synthesizing pesticides, dyes and spices.”[1].

[Audio] Introduction (Cont.) EAS Nitration Reaction: Aromatic rings undergo nitration through the electrophilic aromatic substitution mechanism. When treated with nitric acid (HNO₃) and a strong acid like sulfuric acid (H₂SO₄), aromatic rings form the nitronium ion (NO₂⁺), which acts as the active electrophile. Products: Ortho-, meta-, and para-nitroacetophenone. Significance: Understanding the reaction pathways, mechanisms, and energy profiles of this nitration provides valuable insights into the reactivity and selectivity of acetophenone. This knowledge is essential for optimizing synthetic strategies in organic chemistry..

[Audio] Reaction Pathways Starting Material: Acetophenone (C₆H₅COCH₃) Reagents: Concentrated HNO₃ and H₂SO₄ (nitration mixture) Electrophile: Nitronium ion (NO₂⁺) Nucleophile: Acetophenone Products: Ortho-, meta-, and para-nitro acetophenone (where the meta– product (which is major in the second pattern) directs (called meta-director), and the ortho- and para– products are minor). Figure 1: Nitration of acetophenone with nitric acid (HNO₃) and sulfuric acid (H₂SO₄), producing ortho-, meta- (major), and para-nitroacetophenone. In the second pattern, the meta-product dominates, and the ortho- and para-products are minor. The meta- product is the major product in the nitration of acetophenone because the acetyl group (COCH₃) is an electron-withdrawing group. This group deactivates the benzene ring and directs the nitro group (NO₂) to the meta position, making it more favorable for substitution compared to the ortho and para positions..

[Audio] Reaction Pathways (Cont.) Regioselectivity: Meta product was favored due to the electron-withdrawing nature of the carbonyl (-COCH₃) group. Ortho and para products formed in minor amounts due to steric hindrance and resonance effects. Reaction Equation: Acetophenone to ortho-nitro acetophenone: Acetophenone to meta-nitro acetophenone: Acetophenone to para-nitro acetophenone: Figure 2: Nitration reaction of acetophenone into ortho-, meta, and nitro-acetophenone with nitric acid (HNO₃) and sulfuric acid (H₂SO₄)..

[Audio] EAS Mechanisms – Overview of Nitration Reaction Mechanism Reagents: HNO₃/H₂SO₄ Electrophile: NO₂⁺ Nucleophile: Acetophenone Steps: Sulfuric acid protonates nitric acid. Water leaves protonated nitric acid, forming nitronium ion (NO₂⁺). Aromatic π electrons of acetophenone attack nitronium ion. Products: Ortho-, meta-, and para-nitroacetophenone (where the meta– product (which is major in the second pattern) directs, and the ortho- and para– products are minor)..

[Audio] EAS Mechanisms (Part 2) – Ortho-Nitroacetophenone Mechanism Formation: Reagents: HNO₃/H₂SO₄ Electrophile: NO₂⁺ Nucleophile: Acetophenone Steps: Sulfuric acid protonates nitric acid. Water leaves protonated nitric acid, forming nitronium ion (NO₂⁺). Aromatic π electrons of acetophenone attack nitronium ion at the ortho position. Product: Ortho-nitro acetophenone (minor) Figure 3: Mechanism of acetophenone nitration to form ortho-nitroacetophenone. The nitronium ion (NO₂⁺) formed from HNO₃ and H₂SO₄ attacks the benzene ring, forming a sigma complex intermediate. Deprotonation restores aromaticity, yielding ortho-nitroacetophenone..

[Audio] EAS Mechanisms (Part 3) – Meta-Nitroacetophenone Mechanism Formation: Reagents: HNO₃/H₂SO₄ Electrophile: NO₂⁺ Nucleophile: Acetophenone Steps: Sulfuric acid protonates nitric acid. Water leaves protonated nitric acid, forming nitronium ion (NO₂⁺). Aromatic π electrons of acetophenone attack nitronium ion at the meta position. Product: Meta-nitro acetophenone (major) Figure 4: Mechanism of acetophenone nitration to form meta-nitroacetophenone. The nitronium ion (NO₂⁺) generated from HNO₃ and H₂SO₄ attacks the aromatic ring at the meta position, forming a sigma complex. Deprotonation yields meta-nitroacetophenone. The meta- product is favored over the ortho- product in the nitration of acetophenone because the electron-withdrawing acetyl group (COCH₃) deactivates the benzene ring and directs the nitro group (NO₂) to the meta position. This makes the meta position more favorable for substitution due to increased stability and reduced steric hindrance..

[Audio] EAS Mechanisms (Part 4) – Para-Nitroacetophenone Mechanism Formation: Reagents: HNO₃/H₂SO₄ Electrophile: NO₂⁺ Nucleophile: Acetophenone Steps: Sulfuric acid protonates nitric acid. Water leaves protonated nitric acid, forming nitronium ion (NO₂⁺). Aromatic π electrons of acetophenone attack nitronium ion at the para position. Product: Para-nitroacetophenone (minor) Figure 5: Nitration of acetophenone to form para-nitroacetophenone. The nitronium ion (NO₂⁺) generated from HNO₃ and H₂SO₄ reacts with acetophenone, forming a sigma complex. Deprotonation yields para-nitroacetophenone. The para- product is significant because it forms a stable intermediate, experiences less steric hindrance, and often has favorable physical properties like polarity and solubility..

[Audio] HOMO/LUMO Profiles Graphical representation of reaction coordinate diagrams. Energy barriers for ortho, meta, and para nitration. Stability of intermediates and final products. Interpretation of data from computational chemistry analysis. Meta substitution has the lowest energy barrier, making it the most favored pathway. Graph Interpretation: Reactant Energy Level: All pathways start at the same energy level. Transition State Energies: Meta (orange) has the lowest activation energy, making it the most favorable. Ortho (blue) and para (green) have higher activation energies due to steric and electronic effects. Intermediate Energy Levels: Para (green) has the lowest intermediate energy, making it more stable than ortho and meta. Final Product Stability: Meta (orange) is the most stable final product, aligning with its lower activation barrier. Ortho (blue) and para (green) products are higher in energy, explaining their lower yields. Conclusion: Meta is the major product due to the lowest activation barrier and most stable intermediate. Figure 6: Energy profile of the nitration reaction showing HOMO/LUMO levels for ortho (blue), meta (orange), and para (green) positions. The transition state has the highest energy peak for ortho. The intermediate stage shows a sharp energy drop before stabilizing. Energy levels matter because they determine the stability and feasibility of the reaction. Lower energy levels indicate more stable intermediates and products, while higher transition state energy means higher activation energy is required for the reaction to proceed..

[Audio] HUMO/LUMO Graphics HOMO (Highest Occupied Molecular Orbital): Represents electron-donating ability. LUMO (Lowest Unoccupied Molecular Orbital): Represents electron-accepting ability. Energy values of HOMO and LUMO for: NO2+ (Electrophile) HOMO: -13.777 eV LUMO: -12.267 eV Egap = (LUMO-HOMO) = -12.267 eV –(-13.777 eV) = 1.51 eV Acetophenone (Nucleophile) HOMO: -12.597 eV LUMO: -9.990 eV Egap = (LUMO-HOMO) = -9.990 eV –(-12.597 eV) = 2.61 eV.

[Audio] HOMO/LUMO Graphics (Cont.) Molecular orbital diagrams of HOMO/LUMO of: NO2+ LUMO HOMO Acetophenone LUMO HOMO -12.267 eV Figure 7: HOMO/LUMO energy levels for NO2+ and Acetophenone. NO2+: LUMO -12.267 eV, HOMO -13.777 eV, Egap 1.51 eV. Acetophenone: LUMO -9.990 eV, HOMO -12.597 eV, Egap 2.61 eV. Egap = 1.51 eV -13.777 eV -9.990 eV Egap = 2.61 eV -12.597 eV HOMO and LUMO energy levels were determined for NO2+ and Acetophenone. NO2+ has a smaller energy gap (1.51 eV), indicating higher reactivity. Acetophenone has a larger energy gap (2.61 eV), indicating greater stability. These values help predict molecular behavior in chemical reactions..

[Audio] HOMO/LUMO Energies Electrophile / Nucleophile HOMO Energy (eV) LUMO Energy (eV) Electrophile 1 -5.8 2.3 Electrophile 2 -5.7 2.4 Nucleophile 1 -6.0 2.2 Nucleophile 2 -5.9 2.1 Table summarizing HOMO/LUMO energy values: Electrophiles: Electrophile 1: More reactive acceptor with higher LUMO energy (2.3 eV); less stable donor with lower HOMO energy (-5.8 eV). Electrophile 2: Slightly more stable donor (HOMO = -5.7 eV) but less reactive as an acceptor (LUMO = 2.4 eV). Nucleophiles: Nucleophile 1: More stable donor (HOMO = -6.0 eV) and lower reactivity overall; LUMO energy = 2.2 eV. Nucleophile 2: Slightly less stable donor (HOMO = -5.9 eV) but more reactive acceptor (LUMO = 2.1 eV). Key Takeaway: HOMO Energy: Indicates donor stability; lower values = more stability. LUMO Energy: Reflects acceptor reactivity; higher values = more reactivity. Figure 8: HOMO and LUMO energy values for electrophiles and nucleophiles. Electrophile 1: HOMO -5.8 eV, LUMO 2.3 eV. Electrophile 2: HOMO -5.7 eV, LUMO 2.4 eV. Nucleophile 1: HOMO -6.0 eV, LUMO 2.2 eV. Nucleophile 2: HOMO -5.9 eV, LUMO 2.1 eV. Electrophile 2 and Nucleophile 2 are more reactive. Electrophile 2 is more reactive because it has a higher LUMO energy (2.4 eV), making it easier to accept electrons. Nucleophile 2 is more reactive because it has a higher HOMO energy (-5.9 eV), making it easier to donate electrons. Higher LUMO and HOMO energies generally indicate greater reactivity in electrophiles and nucleophiles, respectively..

[Audio] Conclusion The nitration of acetophenone primarily yields the meta product due to the electron-withdrawing nature of the carbonyl group. Computational and HOMO/LUMO analyses support this selectivity, indicating that the meta pathway has the lowest activation energy and the most stable intermediate. This study underscores the effective collaboration between experimental and computational chemistry in enhancing organic synthesis..

[Audio] References Zhu, J.; Zhao, F.; Meng, J.; Li, Y. Preparation Method of Nitroacetophenone. CN109232259B, May 28, 2021..