Recent Advances in Chlorination: Novel Reagents and Methods from the Last Decade

Abstract

Chlorinated compounds are vital in organic synthesis, impacting nucleophilic substitutions, β-elimination, and C–H acidity. Herein, recent advances in (hetero)arene chlorination, focusing on novel reagents and methods developed in the past decade, are showcased. Traditional electrophilic agents such as Cl₂ and PCl₅ have been expanded with new chlorinating agents such as Palau’chlor, as well as with electrochemical and photochemical techniques. Biocatalyzed chlorination using FAD-dependent halogenases has also been explored. Key trends include green chemistry with eco-friendly chlorine sources like NaCl and HCl. Although nucleophilic chlorination remains rare, electrochemical methods show promise, despite equipment limitations. This graphical review highlights significant progress in the last decade towards more sustainable and efficient chlorination strategies.

Key words

(hetero)arene chlorination - electrophilic substitution - nucleophilic chlorination - chlorinating agents - electrochemistry - photocatalysis - biocatalysis - green chemistry

Biographical Sketches

Iago Vogel (center) was born in São Paulo, Brazil. He earned his B.Sc. degree in biochemistry from the University of Aveiro, Portugal, in 2023, where he completed his final project in organic chemistry under the mentorship of Professors Nuno Candeias (right) and Diana Pinto (left). He subsequently began a master’s program in chemistry at the same university, where he was awarded the Novos Talentos Gulbenkian Scholarship. Currently, in the second year of his master’s studies, Iago’s thesis builds on his undergraduate research, focusing on enhancing the complexity of natural products for medicinal chemistry applications.

Chlorinated compounds are pivotal in organic synthesis, playing key roles in reactions such as nucleophilic substitutions, β-eliminations, and increasing C–H acidity. Chlorination significantly alters the physical and chemical properties of organic molecules, making it a valuable tool in drug development and materials science. Most often, chlorine sources act as electrophiles in these transformations.

Traditional electrophilic chlorinating agents such as Cl₂, sulfuryl chloride (SO₂Cl₂), antimony pentachloride (SbCl₅), phosphorus pentachloride (PCl₅), and tert-butyl hypochlorite (tBuOCl), though effective, present challenges due to their high toxicity and reactivity. Similarly, widely used reagents such as N-chlorosuccinimide (NCS), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), trichloroisocyanuric acid (TCCA), and iodobenzene dichloride (PhICl₂) offer poor atom economy and generate excessive waste.

This graphical review highlights key advancements in the chlorination of organic molecules, particularly (hetero)arenes, over the past decade, with a focus on the development of novel chlorinating reagents. The progress in direct chlorinating agents—where the chlorine source is embedded within the structure of the reagent—is emphasized, along with emerging electrochemical and photochemical methods that utilize electrons and photons as reagents. In addition, this graphical review examines new mediators and catalysts that activate established chlorinating agents such as NCS, DCDMH, SO₂Cl₂, phosphorus(V) oxychloride (POCl₃), and trimethylchlorosilane (TMSCl), thereby broadening the utility of these readily available chlorine sources. This review also explores nature-inspired biocatalyzed chlorination, showcasing recent progress in this area.

Building on Cui’s review on oxidative chlorination[1a] and Verma’s review on general C–H chlorination,[1b] this work shifts the focus towards aromatic chlorination, introducing new direct chlorinating agents, electrochemical methods, and biocatalysis. While there is overlap with previous reviews, this work provides a more expansive and detailed exploration of advanced chlorination techniques.

Each figure in this graphical review presents a novel chlorinating reagent, reaction conditions, substrate scope, and a detailed analysis of the mechanisms and catalytic cycles in order to enhance the understanding of these transformations.

Figure 1 Diverse applications of Palau’chlor (chlorobis(methoxycarbonyl)guanidine)[1`] [d] [e] [f] [g] [h]

Figure 2 Diverse applications of CFBSA (N-chloro-N-fluorobenzenesulfonylamine)[2`] [b] [c] [d] [e]

Figure 3 Diverse applications of CMOBSA (N-chloro-N-methoxybenzene sulfonamide)[3]

Figure 4 Chlorination reactions using NCBSI (N-chloro-N-(phenylsulfonyl)benzene sulfonamide) as the chlorinating agent[4`] [b] [c] [d] [e]

Figure 5 Recent chlorination methods based on the use of the hypervalent iodine reagents PIFA (bis(trifluoroacetoxy)iodo)benzene) and PIDA (phenyliodine(III) diacetate) (part 1)[5`] [b] [c] [d] [e] [f] [g] [h]

Figure 6 Recent chlorination methods based on the use of the hypervalent iodine reagents PIFA (bis(trifluoroacetoxy)iodo)benzene) and PIDA (phenyliodine(III) diacetate) (part 2)[5c] ^, [5`] [j] [k] [l]

Figure 7 Electrochlorination of (hetero)arenes (part 1)[6`] [b] [c] [d] [e] [f] [g]

Figure 8 Electrochlorination of (hetero)arenes (part 2)[6`] [i] [j] [k] [l] [m] [n] [o] [p] [q] [r] [s]

Figure 9 Photochlorination of (hetero)arenes (part 1)[7`] [b] [c] [d] [e]

Figure 10 Photochlorination of (hetero)arenes (part 2)[7`] [g] [h] [i] [j] [k] [l] [m]

Figure 11 Sulfoxide-mediated chlorination of (hetero)arenes (part 1)[8`] [b] [c] [d] [e]

Figure 12 Sulfoxide-mediated chlorination of (hetero)arenes (part 2)[8`] [g] [h] [i] [j]

Figure 13 Amine-catalyzed chlorination of (hetero)arenes[9`] [b] [c] [d] [e] [f]

Figure 14 Thianthrenium-aided chlorination of arenes[10a] [b]

Figure 15 Monochlorination of (hetero)arenes with electrophilic chlorosulfonium species[11a] [b]

Figure 16 Oxone-mediated chlorination of (hetero)arenes[12`] [b] [c] [d] [e]

Figure 17 Tungstate-catalyzed chlorination of (hetero)arenes[13a] [b]

Figure 18 Selectfluor-mediated chlorination of 2-aminopyridines and 2-aminodiazines with LiCl[14`] [b] [c] [d]

Figure 19 Iron(III)-mediated chlorination of arenes[15`] [b] [c] [d]

Figure 20 Chlorination of (hetero)arenes using various catalysts (part 1)[16`] [b] [c]

Figure 21 Chlorination of (hetero)arenes using various catalysts (part 2)[16`] [e] [f]

Figure 22 Biocatalyzed chlorination of (hetero)arenes (part 1)[17`] [b] [c] [d] [e] [f] [g]

Figure 23 Biocatalyzed chlorination of (hetero)arenes (part 2)[17`] [i] [j] [k] [l] [m]

In conclusion, recent advances in (hetero)arene chlorination have introduced a wide variety of novel reagents and methodologies that have significantly expanded the scope of this field. Most contemporary methods rely on electrophilic aromatic substitution (S_EAr), with direct chlorinating agents such as Palau’chlor, CFBSA, CMOBSA, and NCBSI as key examples. Other approaches, including sulfoxide-mediated, amine-catalyzed, and various other catalyzed processes, also utilize this mechanism. In biocatalysis, FAD-dependent halogenases are exclusively used for electrophilic chlorination.

In contrast, some innovative methods involve chlorination through nucleophilic aromatic substitution (S_NAr). These include electrochemical and photocatalytic processes, Selectfluor-mediated halogenation of 2-aminopyridines and 2-aminodiazines, and Oxone- and Fe(III)-mediated chlorination. Additionally, Ni-catalyzed chlorination operates through ligand exchange and reductive elimination.

A notable trend is the integration of green chemistry principles, with many methods utilizing readily available and environmentally benign chlorine sources such as NaCl, LiCl, KCl, MgCl₂, and HCl. This shift towards sustainable practices reflects the broader movement in chemical synthesis towards minimizing environmental impact and increasing practicality.

Despite these advances, nucleophilic chlorination remains relatively rare, often requiring the presence of electron-donating groups (EDGs) on the arene moiety, which can limit the range of substrates. Electrochemical methods are particularly noteworthy for their versatility and capability of minimizing the environmental footprint, using simple and accessible chlorine sources with minimal waste. However, their practical application is constrained by the need for specialized electrochemical equipment.

Overall, the recent progress in chlorination techniques highlights a significant evolution towards greater efficiency and sustainability, with emerging methods improving both the atom economy and the environmental impact.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 23 September 2024

Accepted after revision: 18 October 2024

Accepted Manuscript online:
21 October 2024

Article published online:
19 December 2024