Developments in the Dehydrogenative Electrochemical Synthesis of 3,3',5,5'-Tetramethyl-2,2'-biphenol

Abstract

The symmetric biphenol 3,3',5,5'-tetramethyl-2,2'-biphenol is a well-known ligand building block and is used in transition-metal catalysis. In the literature, there are several synthetic routes for the preparation of this exceptional molecule. Herein, the focus is on the sustainable electrochemical synthesis of 3,3',5,5'-tetramethyl-2,2'-biphenol. A brief overview of the developmental history of this inconspicuous molecule, which is of great interest for technical applications, but has many challenges for its synthesis, is provided. The electro-organic method is a powerful, sustainable, and efficient alternative to conventional synthesis to obtain this symmetric biphenol up to the kilogram scale. Another section of this article is devoted to different process management strategies in batch-type and flow electrolysis and their respective advantages.

Keywords: C−C coupling; electrochemistry; oxidation; polycycles; sustainable chemistry.

Figure 1

A selection of powerful ligands with 2 as a building block.[ ⁵ , ⁶ , ⁷ ]

Scheme 1

General synthesis of 2 by the dehydrogenative conversion of 1.

Figure 2

An overview of different electrolyte conditions for the formation of 2. BDD: boron‐doped diamond, HFIP: 1,1,1,3,3,3‐hexafluoro‐2‐propanol.

Scheme 2

Electrochemical oxidation of 1 in alkaline media.

Scheme 3

Synthetic approach to template‐controlled biphenol synthesis. ^[34]

Figure 3

Illustration of the liquid structure of the solvent system consisting of HFIP, methanol, and arenes. (Green: fluorinated alkyl groups, red: hydroxyl groups and methanol, light gray: 4‐methylguajacol, dark gray: 1,2,4‐trimethoxybenzene, black: BDD electrodes.) Left: All components. Right: Phenols and electrodes only. Reprint with permission from ref. [48]. Copyright 2019, American Chemical Society.

Figure 4

An overview of the scale‐up methodologies of electrolysis in batch or flow with the cell types that can be used for the individual scaling steps: A) Screening system with eight 5 mL screening cells. ^[53] B) 200 mL beaker‐type electrolysis cell. C) 1500 mL beaker‐type electrolysis cell with bipolar or stacked electrode arrangements. D) 2 cm×6 cm flow electrolysis cell.[ ⁵⁵ , ⁵⁶ ] E) 4 cm×12 cm flow electrolysis cell. ^[57] F) Bipolar pilot flow electrolyzer provided by Eilenburger Elektrolyse‐ und Umwelttechnik GmbH (EUT).

Scheme 4

Electrolysis conditions for the dehydrogenative C−C homocoupling of 1 by using NEt₄Br as an supporting electrolyte in A) a 25 mL beaker‐type electrolysis cell and B) a 1500 mL beaker‐type electrolysis cell. ^[3]

Scheme 5

Electrolysis conditions for the dehydrogenative C−C homocoupling of 1 with MeBu₃NO₃SOMe as a supporting electrolyte for scale‐up in A) a 2 cm×6 cm flow electrolysis cell (flow rate: 2.24 mL min⁻¹, 10 °C), B) a 4 cm×12 cm flow electrolysis cell (flow rate: 8.95 mL min⁻¹, 10 °C), and C) an EUT pilot cell (flow rate: 38.8 mL min⁻¹, 0 °C). ^[60]

Scheme 6

Electrolysis conditions for the supporting‐electrolyte‐free dehydrogenative C−C homocoupling of 1 in A) 2 cm×6 cm (flow rate: 3.58 mL min⁻¹, 20 °C) and B) 4 cm×12 cm (flow rate: 14.33 mL min⁻¹, 0 °C) flow electrolysis cells. ^[61]

Figure 5

Schematic overview of the workup strategy for 2 on a technical scale in supporting‐electrolyte‐containing electrolysis. EE: ethyl acetate.

Scheme 7

Postulated pathway for the electrochemical formation of polycyclic byproducts.[ ³² , ⁶³ , ⁶⁴ ]

Scheme 8

Postulated mechanism for the anodic formation of 2 and oligomeric byproducts.[ ²⁵ , ⁴⁴ ]

Figure 6

Atmospheric pressure chemical ionization (APCI) mass spectra of a reaction mixture from the electrolysis of 1 (m/z 120) to 2 (m/z 241). There are signal sets at regular intervals of m/z 120. These correspond to 2 plus further units of 1, so the signal set marked “2+1−2 H” represents the dehydrotrimer 12 and the signal set marked “2+(6×1)−12 H” is a dehydrooctamer. ^[3] .

Scheme 9

Quinoidic and brominated byproducts.

Figure 7

A) Cross section of the cathodic side of a 2 cm×6 cm flow electrolysis cell with an inclined stainless‐steel plate electrode. B) Cathode side of a 2 cm×6 cm flow electrolysis cell with a perforated electrode. Adapted from ref. [60].

Figure 8

Schematic depiction of the electrolytic cycling process. The electrolyte is pumped multiple times at high flow rates through the electrochemical flow cell.

Figure 9

A) Schematic depiction of a cascade process. The electrolyte is pumped n times with an n times higher flow rate though the individual flow electrolysis cells. In each cascade step, an n th part of the necessary charge is applied. Reprinted from ref. [60]. B) Schematic depiction of a continuous cascade process. For an n times higher flow rate, n flow cells are arranged in series.