Benzo[1,2,3]Dithiazole Compounds

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Review Review Benzo[1,2,3]dithiazole Compounds: A History of Synthesis and Their RenewedRenewed ApplicabilityApplicability inin MaterialsMaterials andand SyntheticSynthetic Chemistry, OriginatingOriginating fromfrom thethe HerzHerz ReactionReaction

AlexanderAlexander J. Nicholls * andand Ian Ian R.R. Baxendale Baxendale

Department of Chemistry, University of Durham, SouthSouth Road,Road, DurhamDurham DH1DH1 3LE,3LE, UK;UK [email protected]@durham.ac.uk * Correspondence:Correspondence: [email protected]@durham.ac.uk

Abstract: The benzo[1,2,3]dithiazole is a unique heteroaromatic functionality whose conjugatedconjugated profileprofile instils some fascinating electronic properties. This has been historically recognized in the design and manufacture of organic dyes early last century. Although, with the benefitbenefit of increased diagnostic techniques and improved understanding, these structures are attracting greater attention inin additional research settings,settings, including applicationsapplications as organicorganic radicalsradicals andand semiconductors.semiconductors. In addition, the benzodithiazolebenzodithiazole functionalityfunctionality has has been been shown shown to to be be a valuablea valuable synthetic synthetic intermediate intermediate in inthe the preparation preparation of aof variety a variety of other of other privileged privileged aromatic aromatic and heteroaromatic and heteroaromatic targets, targets, many ofmany which of whichare important are important APIs. InAPIs. this In review, this review, the authors the authors aim to criticallyaim to critically analyse analyse the potential the potential applicability applica- of bilitythese compoundsof these compounds to the fields to the of notfields only of small-scalenot only small laboratory-scale laboratory synthetic andsynthetic medicinal and chemistrymedicinal chemistrybut also commercial-scale but also commercial processes-scale andprocess increasinglyes and increasingly materials chemistry. materials chemistry. Nicholls, A.J.; Baxendale, Citation: Nicholls, A.J.; Baxendale, Keywords: thiazole;thiazole; disulfurdisulfur dichloride;dichloride; Herz Herz reaction; reaction; heterocycle heterocycle formation; formation; organic organic radical radical anion; an- I.R. Benzo[1,2,3]dithiazole ion; semiconductor; dye Compounds: A History of Synthesis semiconductor; dye and Their Renewed Applicability inin Materials and Synthetic Chemistry, Originating from the Herz Reaction. Reactions 2021,, 22,, 175–208.x. https://doi.org/ https:// 1. Introduction to Benz Benzo[1,2,3]dithiazoleo[1,2,3]dithiazole Compounds 10.3390/xxxxx doi.org/10.3390/reactions2030013 The benzo[1,2,3]dithiazole is a rare and enigmatic heterocycle (Figure(Figure 11),), whichwhich atat firstfirst glance has has similarity similarity to to the the more more common common benzothiazole benzothiazole structure, structure, with with the thecarbon car- Academic Editors: Silvana Pedatella Academic Editors: Silvana Pedatella bonat the at the2-position 2-position exchanged exchanged for forsulphur sulphur.. In Inaddition addition,, there there also also exists exists the the isomeric and Dmitry Yu. Murzin and Dmitry Yu. Murzin benzo[1,3,2]dithiazole,benzo[1,3,2]dithiazole, which which,, although also also displaying some some similar similar properties properties and and ap- ap- plications [1 [1––4]4],, will will not not be be covered covered in inthis this review review owing owing largely largely to the to differences the differences in syn- in Received: 303 May May 2021 2021 synthesisthesis [5] [(and5] (and from from here here forward forward for for simplicity, simplicity, ‘benzodithiazole’ ‘benzodithiazole’ will will refer refer only only to to the Accepted: 24 June 2021 [1,2,3]dithiazole derivatives). Published: 2928 June 2021 [1,2,3]dithiazole derivatives).

Publisher’s Note: MDPI stays neu- 4 4 4 Publisher’s Note: H MDPI stays neutral 5 3 5 3 3 tral with regard to jurisdictional N S 5 N with regard to jurisdictional claims in 2 2 claims in published maps and institu- S NH published maps and institutional afﬁl- 6 6 2 6 tional affiliations. S S S iations. 7 1 7 1 7 1 Benzo[1,2,3]dithiazole Benzo[1,3,2]dithiazole Benzo[1,3]thiazole

Figure 1. 1.The structureThe structure and parent and numbering parent system numbering for benzo[1, system2,3]dithiazole, for benzo[1,2,3]dithiazole, benzo[1,3,2]dithi- Copyright: © 2021 by the authors. Li- benzo[1,3,2]dithiazoleazole and benzothiazole. and benzothiazole. Copyright:censee MDPI,© 2021Basel, by Switzerland. the authors. LicenseeThis article MDPI, is an Basel,open access Switzerland. article While all but neglectedneglected as aa syntheticsynthetic intermediateintermediate inin APIAPI andand bulk/ﬁnebulk/fine chemicals, Thisdistributed article under is an the open terms access and article con- the valuable electronic properties of the dithiazoledithiazole structures havehave engenderedengendered renewedrenewed distributedditions of the underCreative the Commons terms At- and interest in recent years. As a result, the general benzo[1,2,3]dithiazole structure appears conditionstribution (CC of BY) the license Creative (http://crea- Commons interest in recent years. As a result, the general benzo[1,2,3]dithiazole structure appears roughly equally in both the scientiﬁc and patent literature over the previous ten years Attributiontivecommons.org/licenses/by/4.0/). (CC BY) license (https:// roughly equally in both the scientific and patent literature over the previous ten years as creativecommons.org/licenses/by/ asit did it did in the in thenear near 100 100years years of its of preceding its preceding existence existence [6]. Despite [6]. Despite a renewed a renewed interest interest in the 4.0/). in the compounds recently, much of the synthetic methods and understanding remain

Reactions 2021, 2, Firstpage–Lastpage. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/reactions Reactions 2021, 2, 175–208. https://doi.org/10.3390/reactions2030013 https://www.mdpi.com/journal/reactions Reactions 2021, 2, FOR PEER REVIEW 2

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compounds recently, much of the synthetic methods and understanding remain mostly transcribedmostly transcribed from the from original the original literature literature (early (early-to-mid-to-mid last century). last century). This This review review aims aims to highlightto highlight their their interesting interesting synthetic synthetic chemistry chemistry and andsignpost signpost some some of the of most the most popular popular end- useend-use applications. applications.

1.11.1.. Categorisation Categorisation of Benzo Benzo[1,2,3]dithiazole[1,2,3]dithiazole Compounds The benzo[1,2,3]dithiazole structure structure exists exists most commonly in three different formsforms with vastly different characteristic properties: the benzodithiazolium cation, the neutral compound andand the the benzodithiazoyl benzodithiazoyl radical. radical. All threeAll three are reversibly are reversibly interconverted interconverted through throughsimple chemical simple chemical transformations transformations [4,7]. The [4,7] benzodithiazolium. The benzodithiazolium cation cation is a planar, is a planar, 10-π 10aromatic-π aromatic system system and isand the is most the most facile facile benzo[1,2,3]dithaizole benzo[1,2,3]dithaizole to generate to generate experimentally. experimentally.Supported Supported by a by counterion a counterion (most (most commonly commonly chloride), chloride), it is itgenerically is generically referred referred to to as as a ‘Herza ‘Herz salt,’ salt, and’ and these these compounds compounds are are generally generally amorphous amorphous andand areare sparinglysparingly solublesoluble in most organic solventssolvents andand aqueousaqueous media media unless unless there there are are large large substituents substituents or or counterions counteri- onspresent. present. In suchIn such circumstances, circumstances crystalline, crystalline polymorphs polymorphs have have been been isolated,isolated, allowing analysis of of the the solid solid structure structure by by X X-ray-ray diffraction diffraction (XRD) (XRD) analysis analysis [8] [8. ].The The second second form form of benzo[1,2,3]dithiazoles,of benzo[1,2,3]dithiazoles, the the neutral neutral compounds, compounds, can can normally normally only only form form when when specific speciﬁc substituents areare locatedlocated atat the the 2 2 or or 6 6 positions; positions; otherwise, otherwise the, the molecule’s molecule’s lack lack of conjugationof conjuga- tionmakes makes the structure the structure too high too in high energy. in energy. The most The common most common examples examples being the being 2-sulfoxides the 2- sulfoxidesand 6-malononitrile and 6-malononitrile derivatives. derivatives. These compounds These compounds generally generally replicate replicate the Herz the salts Herz in saltstheir in physical their physical properties properties (high melting (high melting solid, poorsolid, solubility), poor solubility), although although they canthey have can haveextremely extremely different different absorption absorption properties, properties, notably notably the intense-purplethe intense-purple appearance appearance of the of theS-sulfoxides. S-sulfoxides. These These materials materials tend tend to beto bench-stable,be bench-stable whereas, whereas the the Herz Herz salts salts are are found found to togradually gradually hydrolyse hydrolyse to theto the 2-sulfoxides 2-sulfoxides in thein the presence presence of moisture.of moisture. Finally, Finally, there there are theare the11-π 11‘Herz-π ‘Her radicals,’z radicals which,,’ which in contrast,, in contrast are, highlyare highly soluble soluble in a rangein a range of organic of organic solvents. solvents.While unquestionablyWhile unquestionably reactive reactive intermediates, intermediates, they are they often are stable often in degassed,stable in non-polardegassed, nonsolvents-polar and solvents readily and detected readily by detected ESR and by their ESR distinctive and their distinctive absorption absorption spectra. spectra. OveOverall,rall, all three benzo[1,2,3]dithiazole-derivedbenzo[1,2,3]dithiazole-derived structures structures (Figure (Figure2) 2) have have very very differ- dif- ferentent properties, properties with, with each each possessing possessing unique unique and and specialised specialised attributes, attributes resulting, resulting in different in dif- ferentapplications applications in synthesis in synthesis and materials and materials chemistry. chemistry.

H N N N N S S S O S NC S S Cl S S CN Benzodithiazolium Chloride Benzodithiazoyl 'Herz Salt' Stable, neutral benzodithiazoles 'Herz Radical'

Figure 2. The three principal stable forms that benzodithiazole compounds generally exist as.

1.21.2.. Formation Formation and and Characterisation of Benzo Benzo[1,2,3]dithiazole[1,2,3]dithiazole Compounds With the exception of the occasional ring ring-contraction-contraction procedure [[9]9],, benzodithiazole rings (e.g. (e.g.,, 2,, 33)) are are typically typically formed formed using using the the historical historical Herz Herz reaction reaction or or,, to to a a lesser lesser extent extent,, thethe reaction of a 2 2-aminothiophenol-aminothiophenol (e.g. (e.g.,, 3a3a)) with with thionyl thionyl chloride chloride ( (SchemeScheme 11)[) [1010––12]12].. The first first product is the Herz salt, from which other derivatives can be readily generated inin simple, simple, single single-step-step transformations, transformations, which which will will be be discussed discussed in indetail detail later. later. Characteri- Charac- sationterisation of benzodithiazole of benzodithiazole compounds compounds right right across across the series the series has proven has proven challenging challenging due todue variable to variable stabilities, stabilities, purification purification difficulties difficulties and often and often poor poorsolubilities, solubilities, although although all have all fullhave characterisation full characterisation data (the data Herz (the radical Herz radical,, of course of course,, as a solution). as a solution). Historically Historically the Lewis the structuresLewis structures of the first of the Herz first salts Herz and salts neutral and neutral forms were forms reasoned were reasoned by derivatisation by derivatisation (reacting(reacting to form to known form known entities) entities) but were but later were characterised later characterised by elemental by elemental composition composition analysis,analysis, absorbance absorbance spectroscopy, spectroscopy, mass mass spectrome spectrometrytry and andfinally, finally, NMR. NMR. Due Due to the to the nature nature of of the material, the Herz radicals have been identified by ESR spectroscopy, and some solid the material, the Herz radicals have been identified by ESR spectroscopy, and some solid Herz compounds and salts have been further studied by XRD. In general, a review of the Herz compounds and salts have been further studied by XRD. In general, a review of the literature indicates that Herz salts with small monoatomic counterions generate amorphous Reactions R2021eactions, 2, FOR 2021 PEER, 2, FOR REVIEW PEER REVIEW 3 3

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literatureliterature indicates indicates that Herz that salts Herz with salts small with monoatomic small monoatomic counterions counterions generate generate amor- amor- phous solids, but well-resolved structures are available with larger counterions such as phous solids, but well-resolved structures are available with larger counterions− such as SbClsolids,6ˉ ( but4a, well-resolvedFigure 3a) and structures BF4ˉ. There are are available written with descriptions larger counterions of benzodithiazole such as SbCl-2-sulfox-6 (4a, SbCl6ˉ (4a, Figure 3a) and BF4ˉ. There are written descriptions of benzodithiazole-2-sulfox- Figure3a) and BF −. There are written descriptions of benzodithiazole-2-sulfoxides as hav- ides as ideshaving as having‘crystalline’4 ‘crystalline’ forms [7,13,14] forms [7,13,14]; however; however, a published, a published XRD structure XRD structure remains remains ing ‘crystalline’ forms [7,13,14]; however, a published XRD structure remains unavailable. unavailable.unavailable. Instead Instead, there are, there abundant are abundant examples examples of other of solved other neutralsolved neutral benzodithiazole benzodithiazole Instead, there are abundant examples of other solved neutral benzodithiazole structures structuresstructures (e.g., 4b (e.g., Figure, 4b, 3Figureb) [4,8,15] 3b) [4,8,15]. In these. In structures, these structures, the π-interactions the π-interactions from the from ben- the ben- (e.g., 4b, Figure3b) [ 4,8,15]. In these structures, the π-interactions from the benzodithiazole zodithiazolezodithiazole rings are rings readily are readilyapparent apparent from these from flat these molecules flat molecules stacking stacking atop one atop-an- one-an- rings are readily apparent from these ﬂat molecules stacking atop one-another. other. other.

Herz Reaction Herz Reaction(first Stage) (first [9] Stage) [9] H H NH2 NH N H N S2Cl22(7 equiv.) Cl N 2O H O N S2Cl2 (7 equiv.) Cl 2 S O S S S O AcOH, 6h, HCl S AcOH, 6h,Cl S S HClCl Cl S 1 r.t. - 80°Cr.t. - 80°C Cl93% 3 1 2, 2, 93% 3 Formation with Thionyl Chloride Formation with Thionyl Chloride[10] [10] NH H H 2 NHSOCl2 N N 2 SOCl2 Cl N N HCl2O (solvent)(solvent) S S H2O S O S O S HCl S MeO MeO SH Reflux (5Reflux min) min)MeO S MeOHCl S 3a SH (5 MeO MeO3c 3a 3b, 64%3b, 64% 3c

Scheme 1. An example of benzodithiazole formation using both the Herz reaction and with thionyl SchemeScheme 1. An example 1. An example of benzodithiazole of benzodithiazole formation formation using both using the both Herz the reaction Herz reaction and with and thionyl with thionyl chloride [10,16]. chloridechloride [10,16]. [10,16].

t Bu t Bu N N N SbCl6 SbCl S S N 6 NC NC S S S S t S CN Bu tBu S 4bCN 4a 4a 4b

(a) (a) (b) (b) Figure 3. The crystal structures and unit cells of (a) 4,6-di-t-butyl-1,2,3-benzodithiazolium hexachloro-antimony (4a) [8] Figure 3. The crystalFigure structures 3. The and crystal unit structures cells of (a and) 4,6 unit-di- cellst-butyl of- (1,2,3a) 4,6-di--benzodithiazoliumt-butyl-1,2,3-benzodithiazolium hexachloro-antimony hexachloro- (4a) [8] and (b) 6H-1,2,3-benzodithiazol-6-ylidenemalononitrile tetrahydrofuran solvate (4b) [17]. and (b) 6H-1,2,3-benzodithiazolantimony (4a-6)[-ylidene8] andmalononitrile (b) 6H-1,2,3-benzodithiazol-6-ylidenemalononitrile tetrahydrofuran solvate (4b) [17]. tetrahydrofuran solvate (4b)[17]. 2. Synthesis2. Synthesis of Benzodithiazole of Benzodithiazole Compounds Compounds Using theUsing Herz the Reaction Herz Reaction 2. SynthesisAs indicatedAs of indicated Benzodithiazole below (belowScheme (Scheme Compounds2), structures 2), structures Using, such as the, such 2 Herzor 3as, derive Reaction2 or 3, theirderive name their from name the from the chemicalAschemical indicated transformation transformation below (Schemeused in used 2their), structures, in preparation. their preparation. such asNamed2 or Named3 after, derive its after theirdiscoverer, its name discoverer, fromRichard the Richard Herz,chemical theHerz, transformationHerz the reaction Herz reaction was used first inwas patented their first preparation. patented [18] in 1913[18] Named inand 1913 published after and itspublished discoverer,in subsequent in subsequent Richard jour- jour- nalHerz, articles thenal Herz articles10 years reaction 10 later, years was as later, ﬁrstdetailed patentedas detailed [19]. [It18 relates[19]] in. 1913It trelateso andthe reaction publishedto the reaction of invarious subsequent of various anilines journal anilines with with disulfurarticlesdisulfur 10dichloride years dichloride later, (also as known detailed (also knownas [ 19sulphur]. Itas relatessulphur monochloride) to monochloride) the reaction in a medium of in various a medium of anilinesacetic of acid acetic with to acid to disulfur dichloride (also known as sulphur monochloride) in a medium of acetic acid Reactions 2021, 2, FOR PEER REVIEW 4

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form ‘Herz salts,’ e.g., compound 2 (Scheme 2) [20]. These compounds readily and reversibly react with water to form the sulfone structure (faster in the presence of mild alka- toform form ‘Herz ‘Herz salts salts,’,’ e.g., e.g., compound compound 2 (Scheme3 2 (Scheme 2) [20]2)[. These20]. Thesecompounds compounds readily readily and revers- and line) and revert to the Herz chloride salt upon treatment with strong HCl [7]. The S-oxide reversiblyibly react with react water with waterto form to the form sulfone the sulfone structure structure 3 (faster3 (faster in the in presence the presence of mild of mildalka- can be further manipulated to produce other structures [21]; the simplest way is to use 3 alkaline)line) and andrevert revert to the to Herz the Herzchloride chloride salt upon salt upontreatment treatment with strong with strongHCl [7] HCl. The [ 7S].-oxide The alkaline hydrolysisS-oxide3 can, leading be3 furthercan to be ortho furthermanipulated-aminothiophenols, manipulated to produce to produceas other will bestructures other elaborated structures [21] in; thedetail [21 simplest]; thesub- simplest way is way to us ise sequently [22]. Both the intermediate compounds and the final 2-aminothiophenol hydrol- toalkaline use alkaline hydrolysis hydrolysis,, leading leading to ortho to-ortho-aminothiophenols,aminothiophenols, as will as be will elaborated be elaborated in detail in detail sub- ysis products havesubsequentlysequently a variety [22] . [of 22Both ].uses,Both the but intermediate the the intermediate objective compounds cited compounds by andthe literaturethe and final the 2 at-aminothiophenol final the 2-aminothiophenoltime hydrol- was to make scaffolds for use in the synthesis of dyes [19,23]. The combination and reac- hydrolysisysis products products have a havevariety a varietyof uses, of but uses, the butobjective the objective cited by citedthe literature by the literature at the time at tion of aniline ( ) and sulphur monochloride had been reported in a publication substan- thewas1 time to make was scaffolds to make scaffoldsfor use in for the use synthesis in the synthesis of dyes [19,23] of dyes. The [19 ,combination23]. The combination and reac- tially predatingandtion (1873 reactionof— anilinesee Section of (1 aniline) and 2.2) sulphur ( that1) and of the sulphurmonochloride Herz monochloridereaction had [24] been; however had reported been, the reportedin product a publication in a publication substan- was only described as a ‘violet-brown dye’ and was not characterised. substantiallytially predating predating (1873— (1873—seesee Section Section2.2) that 2.2 of) the that Herz of the reaction Herz reaction[24]; however [24]; however,, the product the productwas only was described only described as a ‘violet as- ab ‘violet-brownrown dye’ and dye’ was and not wascharacterised. not characterised. NH H 2 N H2O/Na2CO N S2Cl2 Cl 3 NH S S O H 2 N H2O/Na2CO N AcOH S2ClS2 Conc. HCl/HCl 2O 3 S Cl S Cl S O 1 2 Conc. HCl/H3 O AcOH Cl S 2 Cl S 1 2 3 Scheme 2. The Herz reaction applied to aniline (1). SchemeScheme 2.2. The Herz reaction appliedapplied toto anilineaniline ((11).). The Herz reaction is often accompanied by chlorination of the para position of the benzo[1,2,3]dithiazoleThe relative Herz reaction to the amine, is often incl accompanieduding through by replacement chlorination of of some the para sub-position of the The Herz reaction is often accompanied by chlorination of the para position of the benzo[1,2,3]dithiazole relative to the amine, including through replacement of some substituents, such benzo[1,2,3]dithiazoleas nitro groups that occupy relative this to thesite amine, in the inclanilineuding starting through material replacement [23]. of some sub- The resultant Herzstituents, compounds such as nitro(e.g., groups and that) are occupy reported this sitefor several in the aniline derivatives starting with material [23]. The stituents, such as nitro 2groups3 that occupy this site in the aniline starting material [23]. resultant Herz compounds (e.g., 2 and 3) are reported for several derivatives with isolated isolated yields Thein the resultant literature Herz [14] compounds. However, conclusive(e.g., 2 and proof 3) are of reported the full structure,for several in- derivatives with yields in the literature [14]. However, conclusive proof of the full structure, including cluding the 5-memberedisolated yields ring, in was the notliterature presented. [14]. Instead,However, derivatization conclusive proof, for exampleof the full, structure, in- through hydrolysisthe 5-membered to form the aminothiol ring, was, not and presented. comparison Instead, to alternative derivatization, synthesis for meth- example, through hydrolysiscluding the to 5 form-membered the aminothiol, ring, was and not comparison presented. toInstead, alternative derivatization synthesis, methodsfor example was, ods was used tothrough elucidate hydrolysis the structure. to form The the dithiazole aminothiol ring, and has comparison subsequently to alternative been con- synthesis meth- firmed as correctlyused hypothesised to elucidate theby unanimous structure. The methods dithiazole suchring as XRD has analysis subsequently [25]. been confirmed as correctlyods was used hypothesised to elucidate by unanimous the structure. methods The dithiazole such as XRD ring analysishas subsequently [25]. been confirmed as correctly hypothesised by unanimous methods such as XRD analysis [25]. 2.1. History and Contributions to Understanding and Mechanism 2.1. History and Contributions to Understanding and Mechanism The very first record of the Herz reaction is the aforementioned occurrence in 1873 2.1. HistoryThe very and first Contributions record of the to HerzUnderstanding reaction is and the Mechanism aforementioned occurrence in 1873 [26] [26] when German chemist, Claus, reported mixing aniline with disulfur dichloride, not- whenThe German very first chemist, record Claus, of the reported Herz reaction mixing is aniline the aforementioned with disulfur dichloride, occurrence noting in 1873 a ing a ‘violent’ reaction with a purple compound as the product. The reactivity was com- ‘violent’[26] when reaction German with chemist a purple, Claus compound, reported as mixing the product. aniline The with reactivity disulfur was dichloride, complicated not- plicated by the use of carbon disulphide as the reaction medium, and the benzodithiazole bying the a ‘violent’ use of carbon reaction disulphide with a purple as the reaction compound medium, as the and product. the benzodithiazole The reactivity compound was com- compound was not identified. The first representation of the [1,2,3]dithiazole ring appears wasplicated not identified.by the use Theof carbon first representation disulphide as the of the reaction [1,2,3]dithiazole medium, and ring the appears benzodithiazole in Herz’s in Herz’s patent dating 1914 [18], an impressive feat at the time to correctly identify this patentcompound dating was 1914 not [identified.18], an impressive The first representation feat at the time of to the correctly [1,2,3]dithiazole identify thisring entirelyappears entirely novel heterocycle. At the time of discovery, the mechanism was not well under- novelin Herz’s heterocycle. patent dating At the 1914 time [18] of discovery,, an impressive the mechanism feat at the was time not to wellcorrectly understood, identify with this stood, with littlelittleentirely being being novelrecorded recorded heterocycle. in inthe the original originalAt the literature, time literature, of discovery, other other than than the the themechanism not not-wholly-correct-wholly was-cor- not well claim under- that rect claim that thethestood, S S-S-Cl-S- withCl moiety moiety little shownbeing shown recorded in in the the product product in the originates original originates literature, directly directly from other from the than thedisulfur disulfurthe not -wholly dichloride-cor- dichloride reagent [19] (the Cl is a counterion not associated with a particular S atom). An reagentrect claim [19 that] (the the Cl S is-S a-Cl counterion moiety shown not associated in the product with a originates particular directly S atom). from An attempt the disulfur was attempt was mademadedichloride by by Bezzubets Bezzubets reagent and [19] and Rozina(the Rozina Cl isto to aunderstand understandcounterion thenot the firstassociated first stage stage of ofwith the the areaction reactionparticular [27 S]; atom). however, An [27]; however, their postulation was based on an incorrect Lewis structure for the sulphur theirattempt postulation was made was by based Bezzubets on an and incorrect Rozina Lewis to understand structure for the the first sulphur stage of monochloride the reaction monochloride ( , Figure 4). ([27]5a,; Figure however4). , their postulation was based on an incorrect Lewis structure for the sulphur monochloride (5a, Figure 4). S S S Cl S S S Cl Cl Cl S Cl 5a S 5b Cl Cl Cl Figure 4. The assumed5a Lewis structure of sulphur monochloride5b at the time of the investigation

Figure 4. The assumedby Bezzubets Lewis structure and Rozina, of sulphur5a [27] andmonochloride the currently at the accepted time of Lewis the investigation structure of disulfurby dichloride, Bezzubets and Rozina, 5a [27] and the currently accepted Lewis structure of disulfur dichloride, 5b 5bFigure[28]. 4. The assumed Lewis structure of sulphur monochloride at the time of the investigation by [28]. Bezzubets and Rozina, 5a [27] and the currently accepted Lewis structure of disulfur dichloride, 5b [28]. Later, Gompper et al. attempted to devise a more comprehensive understanding. Their ﬁndings are outlined in summary in Scheme3[ 29]. The initiating step involves the polarised S–Cl bonds, which ensures that the S atom is electrophilic and hence can be Reactionseactions 20212021,, 22,, FORFOR PEERPEER REVIEWREVIEW 55

Reactions 2021, 2 179 Later, Gompper et al. attempted to devise a more comprehensive understanding. Their findings are outlined in summary in Scheme 3 [29][29].. TheThe initiatinginitiating stepstep involvesinvolves thethe polarised S–Cl bonds, which ensures that the S atom is electrophilic and hence can be attacked byby nucleophilicnucleophilic nitrogen. nitrogen. However, However, additional additionalional speculation speculationspeculation that thatthat the aromatic thethe aromaticaromatic chlo- E chlorinationrination occurs occurs by the by actionthethe action of sulphur of sulphur monochloride monochloride (SEAr) (SEAr) was was found found to be to inaccurate, be inaccu- rateandrate,, there and there was nowas account no account for the for factthe thatfact that electron-withdrawing electron--withdrawing groups groups in this in this position posi- weretiontion werewere replaced replacedreplaced by a chloridebyby aa chloridechloride [22]. Although, [22][22].. AlthoughAlthough in general,,, inin general,general, this proposed ththisis proposedproposed sequence sequencesequence proved provedhelpful inhelpful explaining in explaining many of many the experimental of the experimental results, itresults, was but it was a beginning but a beginning to the full to theunderstandingthe fullfull understandingunderstanding of the sequence. ofof thethe sequence.sequence.

Cl S S2Cl2 S S S2Cl2 2 2 S -HCl-HCl S 2 2 S S NH N S N 1 NH22 N H 1 H H

Cl S Cl S S S2Cl2 S S 2 2 S N N N Cl H 2

Scheme 3. TheThe first ﬁrst postulated postulated sequence sequence of intermediates of intermediates in the in Herz the Herz reactionction reaction fromfrom from GompperGompper Gompper et al. [29]et[29] al... [29].

InIn aa successivesuccessive publicationpublication by by HuestisHuestis et al.al. [[16][16]16],,, studiesstudies werewere conductedconducted toto betterbetter understand thethe aromatic chlorinationchlorination eventevent ofof thethe process.process. AA systematic investigationinvestigation waswas undertaken with the aimaim toto ﬁrstfirst establishestablish whetherwhether thethe non-chlorinatednon--chlorinatedted 1,2,3-dithiazole1,2,31,2,3--dithiazole 2a (Scheme((Scheme 44,,, 2a))) waswas was anan an intermediate.intermediate. intermediate. ThisThis This waswas was achievedachieved achieved byby reactingreacting by reacting thesethese these (previously(previously (previously syn-syn- synthesised) compounds directly under the conditions of the Herz reaction. Thus, hypothe- thesised)thesised) compoundscompounds directlydirectly underunder thethe conditionsconditions ofof thethe HerzHerz reaction.reaction. ThusThus,, hypothe- sising: if the chlorinated product was found, this would add credence that the chlorination sising: if the chlorinated product was found, this would add credence that the chlorination was promoted by disulfur dichloride and that the chlorination was occurring after the was promoted by disulfur dichloride and that the chlorination was occurring after the initial formation of the 1,2,3-dithiazole (e.g., 2a)[16]. This is one of the ﬁrst reports of a initialinitial formationformation ofof thethe 1,2,31,2,3--dithiazole (e.g.(e.g.,, 2a)) [16][16].. ThiThis is one of the first reports of a mechanistic investigation into the Herz reaction, and although the conclusions are limited, mechanistic investigation into the Herz reaction,, and although the conclusions are limited, it was determined that this structure (Scheme4, 2a) was not intermediate because it did itit waswas determineddetermined thatthat thisthis structurestructure ((Scheme 4,, 2a)) waswas notnot intermediateintermediate becausebecause itit diddid not react under these conditions [16]. not react under these conditions [16][16].. N S Cl N N S22Cl22 N S S S Cl AcOH S Cl Reactions 2021, 2, FOR PEER REVIEW S Cl Cl S Cl 6 2a 2

Scheme 4. A ﬁnding of Huestis et al. that suggests 2a is not an intermediate of the Herz reaction [16]. Scheme 4. A finding of Huestis et al. thatthat suggestssuggests 2a isis notnot anan intermediateintermediate ofof thethe HerzHerz reactionreaction lium[16]. group deactivates the ring towards electrophilic substitution as it is electron defi- [16]. A subsequent study by Hope et al. deﬁnes the Herz reaction in terms of three separate stagescient. While [22]. The the stageschlorination were: of a vacant para position was still believed to be an electro- philicA mechanism, subsequent studythe replacement by Hope et ofal. otherdefines groups the Herz by chloridereaction inwas terms instead of three proposed separate as (1) Formation of the 5-membered 1,2,3-dithiazole ring. stagesa nucleophilic [22][22].. TheThe substitution, stagesstages were:were: occurring due to the presence and activation by the electron- (2) Chlorination of the carbon para to the amine (if possible) or replacement of electron- withdrawing(1) Formation benzodithiazolium. of the 5-membered This 1,2,3 reasoning-dithiazole represents ring. a significant improvement in (1) Formationwithdrawing of the groups 5-membered that are ortho 1,2,3or-dithiazolepara to the ring. amine (Scheme5). comprehension,(2) Chlorination and of theit was carbon correct para to to deduce the amine that S(if2Cl possible)2 is not the or directreplacement source ofof electronthe chlo-- (3)(2) ChlorinationOxidation of of the the thiophenol carbon para sulphur to the to amine form (if the possible) salt. or replacement of electron- ride, but it was still not understood how the chloride actually originated. withdrawing groups that are ortho or para toto thethe amineamine ((Scheme 5).). (3)(3) Oxidation of the thiophenol sulphur toto formform thethe salt.salt. NO O2N Cl Cl 2 Cl 2 Interestingly,Interestingly, theythey discovereddiscovered thatthat freefree chlorinechlorine (Cl(Cl2)) waswas presentpresent inin thethe reactreactionion andand N N N deduced that this was more likely to be the chlorinating agent for the ring, as sulphur S S S monochloride is notCl sufficiently electrophilic (at the chlorides) to act as a powerful chlo- MeO S MeO S MeO S Cl rinatingrinating agentagent6a [22][22].. TheyThey alsoalso concludedconcluded thatthat thethe chlorinationchlorination stagestage cannotcannot6b occuroccur afterafter thethe

Herz salt 2 has already formed, as previously suggested by Huetis, because the azathio- Scheme 5.5. The replacement of electron-withdrawingelectron-withdrawing (but notnot electron-donating)electron-donating) substituentssubstituents by chloride.

Interestingly,This new hypothesis they discovered by Hope thatinvolving free chlorine a free chloride (Cl2) was ion present undergoing in the reactionnucleophilic and deducedsubstitution that of this a group was moreon the likely ring, torather be the than chlorinating electrophilic agent substitution for the ring, by disulfur as sulphur dichloride, is supported by results obtained when free Br2 was added to the reaction mixture during the Herz reaction resulting in the isolation of the Herz bromide salt as the product (Scheme 6) [22]. This led to the theory that the aromatic C–Cl bond forms not from reaction with S2Cl2 but with Cl2. The observation that Cl2 could be detected in the conditions of the Herz reactions made this more likely [22].

NO2 Cl NH2 S2Cl2 N AcOH S Cl MeO MeO S 6c 6b

NO2 Br NH2 S2Cl2, Br2 N AcOH S Br MeO MeO S 6c 6d

Scheme 6. The effect of using bromine in addition with the normal Herz reaction conditions on the major product isolated.

The detection of free Cl2 in the reaction could originate from the direct equilibrium of S2Cl2, although this was considered unlikely compared to the liberation of free Cl2 by reaction with the protonated structure 2c (Scheme 7). The process is likely prevalent enough for the mechanism to proceed, provided the sulphur monochloride is in excess (which it is in every recorded literature example, typically 5–7 equivalents is used).

Cl S S H S H S N Cl N Cl S S Cl S Cl S Cl 2b 2c Cl 2

Scheme 7. The postulated mecahnism to explain the generation of Cl2 [22]. Reactionseactions 20212021,, 22,, FORFOR PEERPEER REVIEWREVIEW 66

liumlium groupgroup deactivatesdeactivates thethe ringring towardstowards electrophilicelectrophilic substitutionsubstitution asas itit isis electronelectron defi-deficient. While the chlorination of a vacant para position was still believed to be an electrophilic mechanism, the replacement of other groups by chloride was instead proposed as Reactions 2021, 2 a nucleophilic substitution, occurring due to the presence and activation by the electron180-- withdrawing benzodithiazolium. This reasoning represents a significant improvement in comprehension, and it was correct to deduce that S22Cl22 isis notnot thethe directdirect sourcesource ofof thethe chlo-chloride, but it was still not understood how the chloride actually originated. ride,monochloride but it was isstill not not sufficiently understood electrophilic how the chloride (at the chlorides)actually originated. to act as a powerful chlorinating agent [22]. They also concluded that the chlorination stage cannot occur after NO O2N Cl Cl the HerzNO salt22 2Clhas already formed,2 as previously suggested by Huetis,Cl because the aza- thiolium groupN deactivates the ring towardsN electrophilic substitutionN as it is electron deficient. While theS chlorination of a vacant paraS position was still believedS to be an elec- S Cl S S Cl trophilicMeO mechanism,S the replacementMeO of otherS groups by chlorideMeO was insteadS Cl proposed as 6a 6b a nucleophilic substitution, occurring due to the presence and activation by the electron- Schemewithdrawing 5. The benzodithiazolium.replacement of electron This--withdrawing reasoning (but represents not electron a significant--donating) substituents improvement by chloride.inchloride. comprehension, and it was correct to deduce that S2Cl2 is not the direct source of the chloride, but it was still not understood how the chloride actually originated. This new hypothesis by Hope involving a free chloridechloride ionion undergoingundergoing nucleophilicnucleophilic substitution of of a a group group on on the the ring, ring, rather rather than than electrophilic electrophilic substitution substitution by bydisulfur disulfur dichloride,dichloride, isis supportedsupported is supported byby resultsresults by results obtainedobtained obtained whenwhen when freefree BrBr free22 was Br added2 was to added the reaction to the reactionmixture duringmixture the during Herz the reaction Herz reactionresulting resulting in the isolation in the isolation of the Herz of the bromide Herz bromide salt as the salt product as the (product(Scheme (Scheme6)) [22][22].. ThisThis6)[ ledled22]. totoThis thethe theorytheory led to thatthat the the theorythe aromaticaromatic that the CC–Cl aromatic bond forms C–Cl not bond from forms reaction not withfrom S reaction22Cl22 but with Cl S2Cl22.. TheThe2 but observationobservation with Cl2. The thatthat observation ClCl22 could be that detected Cl2 could in the be conditions detected inof thethe Herzconditions reactions of the made Herz this reactions more likely made [22][22] this.. more likely [22].

NO Cl NO22 Cl NH S Cl NH22 S22Cl22 N S Cl AcOH S Cl S MeO MeO 6b S 6c 6b NO Br NO22 Br NH S Cl Br NH22 S22Cl22,, Br22 N S Br AcOH S Br S MeO MeO S 6c 6d

Scheme 6. The effect of using bromine in addition with the normal Herz reaction conditionsconditions onon thethe major product is isolated.olated.

The detection of free Cl in the reaction could originate from the direct equilibrium The detection of free Cl22 inin thethe reactionreaction couldcould originateoriginate fromfrom thethe directdirect equilibriumequilibrium of S Cl , although this was considered unlikely compared to the liberation of free Cl of S22Cl222,, althoughalthough thisthis waswas consideredconsidered unlikelyunlikely comparedcompared toto thethe liberationliberation ofof freefree ClCl22 by2 reactionbyreaction reaction withwith with thethe the protonatedprotonated protonated structurestructure structure 2c2c ((Scheme(Scheme 77).).). TheThe The process process isisis likelylikelylikely prevalentprevalentprevalent enough for the mechanism to proceed,proceed, providedprovided thethe sulphursulphur monochloridemonochloride is inin excessexcess (which it is in every recorded literature example, typically 5–7 equivalents is used). (which(which itit isis inin everyevery recordedrecorded literatureliterature example,example, typicallytypically 5–7 equivalents is used).

Cl S S H S H S N Cl N N Cl N Cl S S S Cl Cl S Cl S Cl 2b 2c

Cl2 2

Scheme 7. The po postulatedstulatedstulated mecahnism mecahnism to to explain explain the the generation generation of of Cl Cl22 [22][22][22]...

Although Hope correctly reasoned the SNAr of leaving groups with chloride, the explanation for the C–Cl bond formation para to the nitrogen of the Herz compound if unsubstituted relies on electrophilic aromatic substitution with Cl2 (Scheme8). It is unlikely the aromatic ring is sufﬁciently electron-rich for this transformation. There is instead evidence that the chloride attack is much the same whether or not there is a substituent at the para position: SNAr. In summary, Hope’s study came very close to the Reactions 2021, 2, FOR PEER REVIEW 7 R eactions 2021, 2, FOR PEER REVIEW 7

Although Hope correctly reasoned the SNAr of leaving groups with chloride, the ex- Although Hope correctly reasoned the SNAr of leaving groups with chloride, the explanation for the C–Cl bond formation para to the nitrogen of the Herz compound if un- planation for the C–Cl bond formation para to the nitrogen of the Herz compound if unsubstituted relies on electrophilic aromatic substitution with Cl2 (Scheme 8). It is unlikely substituted relies on electrophilic aromatic substitution with Cl2 (Scheme 8). It is unlikely Reactions 2021, 2 the aromatic ring is sufficiently electron-rich for this transformation. There is instead evi-181 the aromatic ring is sufficiently electron-rich for this transformation. There is instead evidence that the chloride attack is much the same whether or not there is a substituent at the dence that the chloride attack is much the same whether or not there is a substituent at the para position: SNAr. In summary, Hope’s study came very close to the correct sequence para position: SNAr. In summary, Hope’s study came very close to the correct sequence but just fell short when it came to explaining the p-chlorination in the absence of another butcorrect just sequencefell short butwhen just it came fell short to explaining when it came the p to-chlorination explaining in the thep-chlorination absence of another in the substituent. substituent.absence of another substituent. Cl S Cl H H NH2 S + HN + HN NH S -H+ N S -H+ N Cl2 S -H S -H S Cl S SS S Cl S 1 Cl 1 Cl Cl Cl Cl H H H HN HN Cl HN Cl Cl2 N N N S Cl S Cl S Cl S 2 S Cl S Cl S Cl S Cl Cl S Cl 2bS Cl S Cl S Cl Cl 2b

N N Cl S Cl S Cl S Cl 2 S 2

SchemeScheme 8.8. The postulation for the mechanism of the Herz reaction by Hope et al. [22]. Scheme 8. The postulation for the mechanism of the Herz reaction by Hope et al. [[22]22].. 2.2.2.2. ProposedProposed MechanismMechanism ofof thethe HerzHerz ReactionReaction 2.2. Proposed Mechanism of the Herz Reaction ToTo date,date, there there still still remains remains no no comprehensive comprehensive model model in thein the literature literature that that accounts accounts for To date, there still remains no comprehensive model in the literature that accounts allfor the all experimentalthe experimental results results as well as well as the as resultingthe resulting overall overall equation equation (Scheme (Scheme9). Therefore, 9). There- for all the experimental results as well as the resulting overall equation (Scheme 9). There- thefore, postulated the postulated mechanism mechanism as shown as shown in Scheme in Scheme 10 is 10 our is attemptour attempt at bringing at bringing together together all fore, the postulated mechanism as shown in Scheme 10 is our attempt at bringing together theall the experimental experimental evidence evidence from from across across the the existing existing literature. literature. all the experimental evidence from across the existing literature. NH N NH 2 N 2 S Cl + 3 S2Cl2 S Cl +4 S + 4 HCl + 3 S Cl Cl S +4 S + 4 HCl 2 2 Cl 2 S Reactions 2021, 2, FOR PEER REVIEW 1 2 8 1 Scheme 9. The balanced equation for the ﬁrst stage of the Herz reaction. Scheme 9. The balanced equation for the first stage of the Herz reaction. Scheme 9. The balanced equation for the first stage of the Herz reaction.

The fundamental difference between this and earlierH propositions is in the carbon- ClThe fundamental Hdifference between this and earlier propositions is in the carbon- chlorination stage, which occurs after oxidation of the sulphur and by a chloride nucleo- S N N NH2 chlorination stage, which occurs after oxidation of the sulphurS and by a chloride nucleo- Sphile rather than some formS of chlorine electrophile. This mechanism does not include the Cl phile rather than some form of chlorine electrophile. This mechanism does not include the role of free Cl2 because thereS is no evidence to suggest this speciesS is critical in the mech- role of free Cl2 because there isCl no evidenceTautomierisation to suggest this to species is critical in the mech- 1 anism, only that it exists as a by-product [22]. It could be that the free Cl2 can also perform anism, only that it exists as a by-product isolateable[22]. It could intermediate be that the free Cl2 can also perform H the chlorination of the sulphurH Cl in 2d as an alternative to the disulfur dichloride. An impli- the chlorination of the sulphur in 2dS as an alternative to the disulfur dichloride. An impli- N Clcation of this mechanismN is that three equivalents-HCl of S2Cl2 are required for the transfor- cation of this mechanism is that three equivalents of S2ClN2 areCl required for the transfor- S mation (typically, more thanS 5 are Sused in the literature). DespiteS the low purchase price S mation (typically, more than 5 areCl used in the literature). Despite the low purchase price of S2Cl2, this could renderS the scheme uneconomical forS many industrial applications, H of S2Cl2, this could render2d the scheme uneconomical for many industrial applications, even more so considering the large sulphur and hydrochloric acid waste (low overall atom even more so considering the large sulphur and hydrochloric acid waste (low overall atom economy). N economy). N Cl S Cl S N S-oxidation S S S Cl S S2Cl2 Cl 2e H 2f N N Cl S Cl S Cl S Cl S H 2

Scheme 10. A new postulated mechanism, taking into account all current literature results to explain the sequence of the Herz reaction.

A difficulty in the compilation of this mechanism was the C–Cl bond formation pertaining to compound 2f when the study by Huetis [16] ruled out 2e as an intermediate by trying to react it directly with S2Cl2. Further developments, such as the practical and computation study by Akulin et al. [10], suggest the feasibility that structure 2e could be attacked by a chloride anion at the 6-position as it carries a partial positive charge of 0.14 eV (Figure 5). The reason that 6-chlorination is observed as part of the complete Herz reaction, but not by Huestis when reacting 2e with S2Cl2 is rationalised by the action of the chloride anion that is required for this phenomenon. The amount of free chloride available is only sufficient when generated during the earlier stages of the Herz reaction and not when 2e is mixed with S2Cl2. Another important aspect of consideration is that in some instances, a thiosulfinyl-aniline (Ar-N=S=S) intermediate is reported in the place of the chloro-disulphide [30–32]. Instinctively we were not keen on the S=S double bonds, although this functionality has several isolated examples when formed under related conditions. The important aspect is that both intermediates are related by simply the elimination of a Cl- ion and thus will both reach the same ring-closed intermediate (2d) [33].

0.09+ N N N N S S S S S S S 0.14+ S 2e

Figure 5. Resonance structures of the benzodithiazolium ion and the computed patrial charges of two carbon atoms in the system [10].

2.3. Scope of Reaction The reaction has been found to work with a wide range of substituted aminophenyls rather than just aniline (1). We have discussed how electron-withdrawing substituents or those with potential leaving group ability (even those that are weak, such as OH/OMe) can be replaced by a chloride ion in nucleophilic substitution, although there are minor mechanistic differences when these groups are present. For groups that cannot behave as a leaving group, such as alkyl groups, the nucleophilic substitution does not happen, and hence, the substituent survives into the product (Scheme 11). Naphthylamines are another Reactions 2021, 2, FOR PEER REVIEW 8

H Cl H S N N NH2 S S S Cl S S Cl to 1 Tautomierisation isolateable intermediate H H Cl N S -HCl Reactions 2021, 2 Cl N N Cl 182 S S S Cl S S S S H 2d

The fundamental difference between this and earlier propositions is in the carbon- N N Cl SchlorinationCl stage, which occursS after oxidation of the sulphurN andS-oxidation by a chloride nucle- S ophile rather than some formS of chlorine electrophile. This mechanismS does not include Cl S Cl the role of free ClCl because there is no evidence to suggestS this species2 2 is critical in the 2 2e H mechanism, only that it exists as a by-product [22]. It could2f be that the free Cl2 can also N perform the chlorination of theN sulphurCl in 2d as an alternative to the disulfur dichloride. S Cl S Cl An implication of this mechanism is that three equivalents of S2Cl2 are required for the S Cl S H transformation (typically,2 more than 5 are used in the literature). Despite the low purchase

price of S2Cl2, this could render the scheme uneconomical for many industrial applications, Scheme 10. A new postulatedeven mechanism, more so considering taking into account the large all sulphurcurrent literature and hydrochloric results to explain acid waste the sequence (low overall of the atom Herz reaction. economy). A difficulty in the compilation of this mechanism was the C–Cl bond formation pertainingA difficulty to compound in the 2fcompilationwhen the studyof this by mechanism Huetis [16] ruledwas the out C2e–Clas anbond intermediate formation bypertaining trying to to react compound it directly 2f when with Sthe2Cl study2. Further by Huetis developments, [16] ruled suchout 2e as as the an practical intermediate and computationby trying to react study it bydirectly Akulin with et al.S2Cl [102. ],Further suggest developments, the feasibility such that as structure the practical2e could and becomputation attacked by study a chloride by Akulin anion et al. at the[10], 6-position suggest the as feasibility it carries that a partial structure positive 2e could charge be ofattacked 0.14 eV by (Figure a chloride5). The anion reason at the that 6-position 6-chlorination as it carries is observed a partial as positive part of thecharge complete of 0.14 HerzeV (Figure reaction, 5). The but reason not by that Huestis 6-chlorination when reacting is observed2e with as part S2Cl of2 is the rationalised complete Herz by the re- actionaction, ofbut the not chloride by Huestis anion when that reacting is required 2e with for thisS2Cl phenomenon.2 is rationalised The by the amount action of of free the chloridechloride availableanion that is is only required sufficient for this when phenomenon. generated duringThe amount the earlier of free stages chloride of theavailable Herz reactionis only sufficient and not when when2e generatedis mixed withduring S2 Clthe2. earlier Another stages important of the aspect Herz ofreaction consideration and not iswhen that in2e someis mixed instances, with S a2Cl thiosulfinyl-aniline2. Another important (Ar-N=S=S) aspect of intermediate consideration is reportedis that in in some the placeinstances, of the a chloro-disulphidethiosulfinyl-aniline [30 (Ar–32-N=S=S)]. Instinctively intermediate we were is reported not keen onin the the place S=S double of the bonds,chloro-disulphide although this [30– functionality32]. Instinctively has severalwe were isolated not keen examples on the S=S when double formed bonds, under alt- relatedhough this conditions. functionality The important has several aspect isolated is that examples both intermediates when formed are under related related by simply condi- − thetions. elimination The important of a Cl aspection is and that thus both will intermediates both reach the are same related ring-closed by simply intermediate the elimina- (tion2d)[ of33 a]. Cl- ion and thus will both reach the same ring-closed intermediate (2d) [33].

0.09+ N N N N S S S S S S S 0.14+ S 2e

FigureFigure 5.5. ResonanceResonance structuresstructures ofof thethe benzodithiazoliumbenzodithiazolium ionion andand thethe computedcomputed patrialpatrial chargescharges ofof twotwo carboncarbon atomsatoms inin thethe systemsystem [[10]10].. 2.3. Scope of Reaction 2.3. Scope of Reaction The reaction has been found to work with a wide range of substituted aminophenyls The reaction has been found to work with a wide range of substituted aminophenyls rather than just aniline (1). We have discussed how electron-withdrawing substituents or rather than just aniline (1). We have discussed how electron-withdrawing substituents or those with potential leaving group ability (even those that are weak, such as OH/OMe) canthose be with replaced potential by a chlorideleaving group ion in ability nucleophilic (even those substitution, that are although weak, such there as areOH/OMe) minor mechanisticcan be replaced differences by a chloride when these ion in groups nucleophilic are present. substitution, For groups although that cannot there behave are minor as a leavingmechanisti group,c differences such as alkyl when groups, these groups the nucleophilic are present. substitution For groups does that notcannot happen, behave and as hence,a leaving the group, substituent such survivesas alkyl groups, into the the product nucleophilic (Scheme substitution 11). Naphthylamines does not happen are another, and suitablehence, the substrate, substituent largely survives forming into the the dithiazole product ( compoundsScheme 11). inNaphthylamines higher yields than are smalleranother substituted anilines [16]. There are a handful of instances where the Herz reaction has been applied successfully to other heteroaromatic structures, such as amino-benzothiophenes giving good yields of the dithiazole adducts [34]. Surprisingly, if the substrate is a 2- and 6-substituted (di-ortho) aniline (e.g., 7a or 7g, Scheme 12), then the Herz reaction still occurs to produce a 1,2,3-dithiazole ring (through an intermediate N-thiosulﬁnylaniline such as 7b), although the aromaticity is inevitably not possible, and hence, there are fewer instances where this reaction has been explored [30,35,36]. To complicate matters further, Inagaki et al. isolated the benzodiathiazole 3c as a yellow, crystalline solid in good yield (70%), although they also observed that this benzodithiazole form (3c) and the N-thiosulﬁnylaniline 7b were interchangeable Reactions 2021, 2 183

in solution [31]. The N-thiosulfinylaniline (7b) was hence not isolated and fully characterised but correlated with existing analytical data to confirm the presence of this moiety (Scheme 12)[37]. This ‘equilibrium’ was later observed using NMR spectroscopy, finding that while the position was highly solvent dependent, the benzodithiazole was generally the dominant structure and that calculation of the enthalpy and entropy of isomerisation from thiosulfinylaniline to benzodithaizole were both negative values [32]. Coincidentally, the first reported XRD structure of a benzo[1,2,3]dithiazole in the Cambridge structural database (Cambridge Crystallographic Data Centre—CCDC) was this precise tri-tert-butyl compound (7c, Scheme 12, Figure6a) [ 25,35]. A similar interconversion phenomenon is observed when one of the ortho-substituents is an ester (e.g., 7g)[38]. These aromaticity- disrupted, 6π benzodithiazole structures (such as 7c and 7i) are privileged in that they are readily reduced by thermolysis to form a 7π neutral radical, with the loss of the group sharing a ring-position with the sulphur. This will be elaborated in Section 2.6[ 4]. Worth noting is that the reactions shown (Scheme 12) were performed in triethylamine/diethyl ether rather than the more popular, mildly-acidic medium of acetic acid. Finally, the Reactions 2021, 2, FOR PEER REVIEW 9 reaction can also be conducted if there is a 2-methyl substituent and the 6-position is blocked (with, e.g., a tBu, 7g), although, in this instance, the resulting N-thiosulfinylaniline intermediate 3e is a stable product that can be isolated as a solid, rather than forming the benzodithiazole.suitable substrate, Its largely structure forming has been the dithiazole confirmed compounds by XRD analysis in higher (Figure yields6b) than [ 39]. smaller If this ortho-substitutedmethyl- anilinesN-thiosulfinylaniline [16]. There are is a heated,handful an of intramolecular instances where reaction the Herz occurs reaction with thehas methylbeen applied substituent, successfully giving to a benzoother isoheteroaromaticthiazole as the structures, major product, such as albeit amino in a-benzothio- quite low yieldphenes (40%) giving as agood large yields proportion of the degradesdithiazole back adducts to the [34] parent. aniline starting material [30].

NH2 N S Cl R= Alkyl R R S

NH2 N S Cl X = Br, X Cl, Cl S OH, NO2 2

Reactions 2021, 2, FOR PEER REVIEWScheme 11. The products of the Herz Reaction if 4 substituted anilines are used as the starting10 Scheme 11. The products of the Herz Reaction if 4 substituted anilines are used as the starting ma- material.terial.

t Surprisingly, if the substrate is a t2Bu- and 6-substituted (di-ortho)Bu aniline (e.g., 7a or 7g, tBu Scheme 12), then the Herz reaction still occursN to produce a 1,2,3-dithiazoleN ring (through NH2 S Room T an intermediate NS-2thiosulfinylanilineCl2 (1 equiv.) such as 7b), although the aromaticityS is inevitably t t S t S nott possible, and henceNEt, 3there areBu fewer instancesBu Solutionwhere thisBu reaction has been explored Bu tBu tBu [30,35,36]7a. To complicate matters further,7b, Not isolated Inagaki et al. isolated7c, the70% benzodiathiazole yield [31] 3c as a yellow, crystalline solid in good yield (70%), although they also observed that this ben- tBu t tBu zodithiazole form (3c) and the N-thiosulfinylanilineBu 7b were interchangeable in solution NH [31]. The N-thiosulfinylaniline2 S2Cl2 (1 equiv.) ( ) was henceN not isolatedToluene and fully characterisedN but cor- 7b S S NEt relatedt with existing analytical3 data to confirmS the70 °C,presence 28 h t of this moiety (Scheme 12) Bu tBu Bu [37]. This7d ‘equilibrium’ was later observed using NMR spectroscopy, finding that while 7e 7f, 40% yield [30] the position was highly solvent dependent, the benzodithiazole wast generally the domi- tBu tBu Bu nant structure and that calculation of the enthalpy and entropy of isomerisation from thi- NH N S N 2 S2Cl2 (1 equiv.) osulfinylaniline to benzodithaizole were bothS negative values [32]. Coincidentally,S the first reported XRDOEt structureNEt3 of a benzo[1,2,3]dithiaOEt zole in thet CambridgeS structural data- tBu t Bu base (Cambridge CrystallographicBu Data Centre—CCDC) was this preciseOEt tri-tert-butyl O 7g O 7i, 73% yield [38] compound (7c, Scheme 12, Figure 7h,6a )Not [25,35] isolated. A similar interconversion phenomenon is observed when one of the ortho-substituents is an ester (e.g., 7g) [38]. These aromaticity- Schemedisrupted, 12. 6πTheThe benzodithiazole synthesis synthesis of ofbenzodithiazole benzodithiazolestructures (such compounds compounds as 7c and from 7i from) are an privileged anorthoortho-disubstituted-disubstituted in that they aniline ani-are [30,31,38]linereadily [30,31 reduced. ,38]. by thermolysis to form a 7π neutral radical, with the loss of the group sharing a ring-position with the sulphur. This will be elaborated in Section 2.6 [4]. Worth noting is that the reactions shown (Scheme 12) were performed in triethylamine/diethyl ether rather than the more popular, mildly-acidic medium of acetic acid. Finally, the reaction can also be conducted if there is a 2-methyl substituent and the 6-position is blocked (with, e.g., a tBu, 7g), although, in this instance, the resulting N-thiosulfinylaniline intermediate 3e is a stable product that can be isolated as a solid, rather than forming the benzodithiazole. Its structure has been confirmed by XRD analysis (Figure 6b) [39]. If this ortho-methyl-N-thiosulfinylaniline is heated, an intramolecular reaction occurs with the methyl substituent, giving a benzoisothiazole as the major product, albeit in a quite low yield (40%) as a large proportion degrades back to the parent aniline starting material [30].

(a) (b) Figure 6. The unit cells of (a) 2,4,6-tri-t-butyl-7,8,9-dithia-azabicyclo(4.3.0)nona-1(9),2,4-triene (7c) [35] and (b) 2,4-di-t- butyl-6-methyl-N-thiosulfinyl-aniline (7e) [39].

2.4. Regioselectivity Based upon our proposed mechanism (Scheme 10), the formation of the dithiazole ring involves both electrophilic and nucleophilic ring attacks. The second step is the aromatic C–S bond formation, from one of two possible ortho positions of the starting aniline (1, Scheme 10). In asymmetric anilines, it is inevitable that additional ring substituents will often cause the new 5-membered ring to form from one preferential ortho carbon. Specifi- cally, one would expect the most electron-rich of the two carbons to perform this attack and become part of the new ring. In a publication by Van-Snick et al. [14], this effect is evident in the compounds prepared (Scheme 13), although such high levels of regioselectivity in the product formation is somewhat unexpected. The more reactive carbon is probably C2 because of electron-donating inductive effects from the C3-alykl chain (Scheme 13, 8c). However, C6 is actually similar to C2, so both may therefore be possible, but the paper claims the C–S bond always forms at C2, and the yield is 77%, with no regioisomers reported. There is no explanation as to why the regioselectivity is so high or any record of the other possible product, 8e. Perhaps this other regioisomer was too challenging to isolate or overlooked as a minor product impurity. The compounds were charac- Reactions 2021, 2, FOR PEER REVIEW 10

t tBu Bu tBu N N NH2 S Room T S2Cl2 (1 equiv.) S t t S t S t NEt3 Bu Bu Solution Bu Bu tBu tBu 7a 7b, Not isolated 7c, 70% yield [31] t t Bu tBu Bu NH 2 S2Cl2 (1 equiv.) N Toluene N S S NEt3 tBu t S 70 °C, 28 h tBu 7d Bu 7e 7f, 40% yield [30] t tBu tBu Bu

NH N S N 2 S2Cl2 (1 equiv.) S S NEt t t OEt 3 t OEt Bu S Bu Bu OEt O 7g O 7i, 73% yield [38] 7h, Not isolated Reactions 2021, 2 184 Scheme 12. The synthesis of benzodithiazole compounds from an ortho-disubstituted aniline [30,31,38].

(a) (b)

FigureFigure 6. 6.The The unit unit cells cells of (ofa) 2,4,6-tri-t-butyl-7,8,9-dithia-azabicyclo(4.3.0)nona-1(9),2,4-triene(a) 2,4,6-tri-t-butyl-7,8,9-dithia-azabicyclo(4.3.0)nona-1(9),2,4-triene (7c)[ 35(7c]) and [35] (b and) 2,4-di-t-butyl- (b) 2,4-di-t- 6-methyl-butyl-6-methylN-thiosulﬁnyl-aniline-N-thiosulfinyl- (aniline7e)[39 ].(7e) [39].

2.4.2.4. Regioselectivity Regioselectivity BasedBased upon upon our our proposed proposed mechanism mechanism (Scheme (Scheme 10 10),), the the formation formation of of the the dithiazole dithiazole ringring involvesinvolves bothboth electrophilic and and nucleophilic nucleophilic ring ring attacks. attacks. The The second second step step is the is thearo- aromaticmatic C– C–SS bond bond formation, formation, from from one one of of two two possible possible ortho positions ofof thethe starting starting aniline aniline (1(1, ,Scheme Scheme 10 10).). In asymmetric asymmetric anilines, anilines, it it is is inevitable inevitable that that additional additional ring ring substituents substituents will willoften often cause cause the new the new5-membered 5-membered ring to ring form to from form one from prefer oneential preferential ortho carbon.ortho carbon. Specifi- Speciﬁcally,cally, one would one would expect expect the most the mostelectron electron-rich-rich of the of two the carbons two carbons to perform to perform this attack this attackand become and become part of part the ofnew the ring. new In ring. a publication In a publication by Van by-Snick Van-Snick et al. [14] et, al. this [14 effect], this is effectevident is evidentin the compounds in the compounds prepared prepared (Scheme (Scheme13), although 13), althoughsuch high such levels high of regioselec- levels of regioselectivitytivity in the product in the formation product is formation somewhat is unexpected. somewhat unexpected.The more reactive The morecarbon reactive is prob- carbonably C2 is because probably of C2electron because-donating of electron-donating inductive effects inductive from the effects C3-alykl from chain the C3-alykl chain(Scheme (Scheme 13, 8c 13). However,, 8c). However, C6 is actually C6 is actually similar similar to C2, so to both C2, somay both therefore may therefore be possible, be possible,but the paper but the claims paper the claims C–S bond the C–Salways bond forms always at C2 forms, and the at C2, yield and is 77%, the yield with isno 77%, regi- Reactions 2021, 2, FOR PEER REVIEW 11 withoisomers no regioisomers reported. There reported. is no explanation There is no explanationas to why the as regioselectivity to why the regioselectivity is so high or an isy sorecord high of or the any other record possible of the product, other possible 8e. Perhaps product, this8e other. Perhaps regioisomer this other was regioisomertoo challeng- wasing tooto isolate challenging or overlooked to isolate oras overlookeda minor product as a minor impurity. product The impurity. compounds The were compounds charac- terisedwere characterised by proton and by carbon proton NMR and carbon spectroscopy, NMR spectroscopy, along with (accurate) along with mass (accurate) spectrom masse- tryspectrometry and IR spectroscopy. and IR spectroscopy. Inspecting Inspecting this data cannot this data confirm cannot beyond conﬁrm doubt beyond that doubt the pro- that posedthe proposed regiochemistry regiochemistry is correctly is correctly assigned. assigned.

Scheme 13. TheThe literature literature claim of Van Van-Snick-Snick et al. [14] [14],, followed followed by by what what would would be be expected expected from from a general general understanding understanding of the theory.

In contrast, the results obtained by Koutentis et al. [40] on substrate 9a instead gave two distinct Herz salts under similar reaction conditions, in a ratio of approximately 2:1 (Scheme 14). The major product is somewhat surprising given the results from Van-Snick, as the carbon that reacts is less activated by the substituents than in the minor product (though the major product could be marginally favoured sterically). The products 9b and 9c (Scheme 14) were not separable but were characterised (from the mixture) and distin- guished by proton and carbon NMR spectroscopy, as well as mass spectrometry.

Me Cl Me NH2 Cl S S S Cl , AcOH 2 2 S Cl + S Cl 9 h, 80 °C N Me N 9a 9b 1:2 9c

Scheme 14. The scheme showing the product distribution obtained by Koutentis et al. [40].

2.5. Formation of Benzo[1,2,3]dithiazole ‘Herz’ Radicals By the final quarter of last century, it might have appeared that research into Herz’s reaction and the properties of benzodithiazole products had been fully exploited; this de- clining interest was rapidly reversed when it was discovered by the German chemist R. Mayer and co-workers that these structures were capable of forming stable radical anions [41]. Following advancements in Electrospray resonance spectroscopy, the new radical species was identified. This discovery was confirmed by Inagaki et al. when heating benzodithiazole structures in degassed benzene and recording a persistent signal, suggesting the existence of a radicalised structure [30]. (Roland’s publications are not listed as references by Inagaki, so it is possible these two discoveries came about independently). The ‘Herz radical’ of the benzene and naphthalene derivatives were then isolated in a solution by Fabian et al. [42], being described as a red and green solution, respectively. The generation of the benzodithiazolium ‘Herz salts’ and subsequent interconversions discussed are thought to largely involve heterolytic processes, though it is the formation of ‘Herz radicals’ that mainly contribute to many of the unique electronic properties and resulting appearances of benzodithiazole structures in the literature. Mayer continued his investigations well into the 1980s, patenting a large number of new radical structures (>50 structures in total) with their measured g values (all between 2.006 and 2.010) [43]. Reactions 2021, 2, FOR PEER REVIEW 11

terised by proton and carbon NMR spectroscopy, along with (accurate) mass spectrometry and IR spectroscopy. Inspecting this data cannot confirm beyond doubt that the proposed regiochemistry is correctly assigned.

Literature scheme Cl O S S S S 2 2 N 2 NH 3 NH2 S Cl 3 NaOH (1M) 3 1 2 2 1 1 EtO C EtO C EtO C 2 AcOH, 0 °C 2 H2O 2 S 4 6 S 4 6 S 4 6 8a 5 5 5 8b 8c Alternative regioisomer product 2 2 3 2 H 3 NH2 S Cl N 3 1 2 2 1 NaOH (1M) N EtO C EtO2C S Cl 1 2 AcOH, 0 °C EtO2C S O S 4 6 S 4 6 S H2O 5 5 S 4 6 S 8a 8d 8e 5 Reactions 2021, 2 185 Scheme 13. The literature claim of Van-Snick et al. [14], followed by what would be expected from a general understanding of the theory.

In contrast, the results obtainedobtained by KoutentisKoutentis et al. [[40]40] onon substratesubstrate 9a9a insteadinstead gavegave two distinct Herz salts under similar reaction conditions,conditions, in a ratioratio ofof approximatelyapproximately 2:1 (Scheme(Scheme 14). The major product is somewhat somewhat surprising surprising given given the the results results from from Van Van-Snick,-Snick, as the carbon that reacts is lessless activatedactivated byby thethe substituentssubstituents than inin thethe minorminor productproduct (though the the major major product product could could be be marginally marginally favoured favoured sterically). sterically). The The products products 9b and9b and9c (Scheme9c (Scheme 14) were 14) werenot separable not separable but were but characterised were characterised (from (fromthe mixture) the mixture) and distin- and distinguishedguished by proton by proton and carbon and carbon NMR NMRspectroscopy, spectroscopy, as well as as well mass as massspectrometry. spectrometry.

Me Cl Me NH2 Cl S S S Cl , AcOH 2 2 S Cl + S Cl 9 h, 80 °C N Me N 9a 9b 1:2 9c

Scheme 14. The scheme showing the product distribution obtainedobtained by KoutentisKoutentis etet al.al. [[40]40].. 2.5. Formation of Benzo[1,2,3]dithiazole ‘Herz’ Radicals 2.5. Formation of Benzo[1,2,3]dithiazole ‘Herz’ Radicals By the final quarter of last century, it might have appeared that research into Herz’s reactionBy the and final the quarter properties of last of benzodithiazolecentury, it might productshave appeared had been that fullyresearch exploited; into Herz’s this decliningreaction and interest the properties was rapidly of benzodithiazole reversed when itproducts was discovered had been by fully the exploited; German chemistthis de- R.clining Mayer interest and co-workerswas rapidly that reversed these when structures it was were discovered capable by of the forming German stable chemi radicalst R. anionsMayer and [41]. co Following-workers that advancements these structures in Electrospray were capable resonance of forming spectroscopy, stable radical the anions new radical[41]. Following species wasadvancements identified. in This Electro discoveryspray resonance was confirmed spectroscopy, by Inagaki the etnew al. radical when heatingspecies was benzodithiazole identified. This structures discovery in degassed was confirmed benzene by and Inagaki recording et al. when a persistent heating signal, ben- suggestingzodithiazole the structures existence in of degassed a radicalised benzene structure and [recording30]. (Roland’s a persistent publications signal, are suggesting not listed asthe references existence byof Inagaki,a radicalised so it isstructure possible [30] these. (Roland’s two discoveries publications came are about not independently). listed as refer- Theences ‘Herz by Inagaki, radical’ so of it the is possible benzene these and naphthalenetwo discoveries derivatives came about were independently). then isolated inThe a solution‘Herz radical’ by Fabian of the et benzene al. [42], and being naphthale describedne as derivatives a red and were green then solution, isolated respectively. in a solution by FabianThe generation et al. [42], ofbeing the benzodithiazoliumdescribed as a red ‘Herzand green salts’ solution and subsequent, respectively. interconversions discussedThe generation are thought of to the largely benzodithiazolium involve heterolytic ‘Herz processes, salts’ and though subsequent it is the interconver- formation ofsions ‘Herz discussed radicals’ are that thought mainly to contribute largely involve to many heterolytic of the unique processes, electronic though properties it is the andfor- resultingmation of appearances‘Herz radicals’ of that benzodithiazole mainly contribute structures to many in the of the literature. unique Mayerelectronic continued proper- histies investigationsand resulting appearances well into the of 1980s, benzodithiazole patenting a largestructures number in the ofnew literature. radical Mayer structures con- (>50tinued structures his investigations in total) with well their into measured the 1980s, g valuespatenting (all betweena large number 2.006 and of 2.010)new radical [43]. structuresThe most (>50 generalstructures method in total) to formwith thetheir Herz measured radical g is values to perform (all between a mild reduction2.006 and of2.010) the [43] Herz. salt (e.g., 2) with, for example, zinc dust in a non-polar solvent, such as hexane [42], although with the presence of particular ring substituents, the reduction can also be achieved electrochemically [44] or even thermally [41,45] (Scheme 15). The radical formation is accompanied by the Herz salt dissolving (becoming much more soluble) and a prominent colour change, with the radical being separated from any remaining Herz salt by the insolubility of the precursor salts in non-polar solvents. The Herz radicals have very distinctive UV/visible absorption spectra, which, along with their solubility properties, sets them apart from the Herz salts [33,42]. Herz salts (e.g., 2) can be regenerated from the radicals by relatively mild oxidation with, for example, Cl2, or coincidentally, disulfur dichloride [33]. The Herz S-oxides (e.g., 3) are also suitable substrates, with a report of a compound forming a Herz radical intermediate after heating at 80 ◦C[37]. This latter species holds interest for potential molecular oxygen-based oxidation sequences, which may be of interest in the formation of reactive oxygen species (ROS) for applications in disinfection and therapeutic treatments [46]. Reactions 2021, 2, FOR PEER REVIEW 12

The most general method to form the Herz radical is to perform a mild reduction of the Herz salt (e.g., 2) with, for example, zinc dust in a non-polar solvent, such as hexane [42], although with the presence of particular ring substituents, the reduction can also be achieved electrochemically [44] or even thermally [41,45] (Scheme 15). The radical formation is accompanied by the Herz salt dissolving (becoming much more soluble) and a prominent colour change, with the radical being separated from any remaining Herz salt by the insolubility of the precursor salts in non-polar solvents. The Herz radicals have very distinctive UV/visible absorption spectra, which, along with their solubility properties, sets them apart from the Herz salts [33,42]. Herz salts (e.g., 2) can be regenerated from the radicals by relatively mild oxidation with, for example, Cl2, or coincidentally, disulfur dichloride [33]. The Herz S-oxides (e.g., 3) are also suitable substrates, with a report of a compound forming a Herz radical intermediate after heating at 80 °C [37]. This latter spe- Reactions 2021, 2 cies holds interest for potential molecular oxygen-based oxidation sequences, which may186 be of interest in the formation of reactive oxygen species (ROS) for applications in disinfection and therapeutic treatments [46].

Mild reductant N Cl (e.g. Zn(0)) N solvent R S Non-polar R S S Mild oxidant (e.g. Cl2) S (2, R = 4-Cl) Herz Radical Mild reductant H N (e.g. Zn(0)) N 80 °C R S O R S S Mild oxidant (e.g. Cl2) S (3, R = 4-Cl) Herz Radical Electrochemical example [44] O O

E = N N OTf cell 0.60 N N S S S S n-Bu NPF S S 4 6 (0.1 S S M in MeCN) Cl Cl 10a 10b

Scheme 15. The formation of Herz radicals from Herz salts (e.g. (e.g.,, 2) or neutral benzodithiazole-2-benzodithiazole-2- sulfoxides (e.g. (e.g.,, 3) and an electrochemical example [[4,44]4,44]..

BenzodithiazolesBenzodithiazoles,, where where the the aromaticity aromaticity has has been been disrupted disrupted,, are are particularly particularly easy easy to π reduceto reduce to the to the radical radical anion. anion. Such Such compounds compounds,, if trapped if trapped in a in 6π a 6configuration,configuration, can can be be reduced to the corresponding 7π radical anions and then again oxidised to the (in reduced to the corresponding 7π radical anions and then again oxidised to the (in some some cases, fully-aromatic) Herz salt using Cl2 [4]. A malononitrile moiety has been cases, fully-aromatic) Herz salt using Cl2 [4]. A malononitrile moiety has been introduced introduced to a Herz salt with ease, and this can be further elaborated (see Section 3.5). to a Herz salt with ease, and this can be further elaborated (see Section 3.5). This dramat- This dramatically activates the ability of the system to accept an electron, to the point ically activates the ability of the system to accept an electron, to the point where the first where the first electron affinity energy was measured as 2.69 electron volts for the entity electron affinity energy was measured as 2.69 electron volts for the entity (11a) shown (11a) shown (Scheme 16)[47,48]. This positive value indicates the compound, 11a, forms (Scheme 16) [47,48]. This positive value indicates the compound, 11a, forms a radical an- a radical anion (11b) that is more thermodynamically stable than the original neutral ion (11b) that is more thermodynamically stable than the original neutral molecule (11a); molecule (11a); not uncommon for various benzodithiazoles, but this value is notably high. not uncommon for various benzodithiazoles, but this value is notably high. The 6-malo- The 6-malonitrile-substituted structure is readily reduced both electrochemically or by a nitrile-substituted structure is readily reduced both electrochemically or by a chemical chemical mixture of bis(toluene)chromium(0) and tetrakis(dimethylamino)ethylene in a mixtureDMF solution. of bis(toluene)chromium(0) Subsequent studies haveand tetra furtherkis(dimethylamino)ethylene increased the electron affinity in a DMF with solu- the Reactions 2021, 2, FOR PEER REVIEWtion. Subsequent studies have further increased the electron affinity with the incorpora-13 incorporation of additional moieties, and these new structures have found valuable uses in tionmany of applications additional moieties in materials, and chemistry these new (see structures Section 5have)[45 ].found valuable uses in many applications in materials chemistry (see Section 5) [45].

N Cr(0) (Toluene)2 N S Tetrakis(dimethyl S NC S amino)ethylene NC S DMF, 2.69 eV CN CN 11a 11b

Scheme 16. The reduction of 6-malonitrile-substituted benzodithiazole to the radical anion [47,48]. Scheme 16. The reduction of 6-malonitrile-substituted benzodithiazole to the radical anion [47,48]. 2.6. Reactions with Multi-Fuctional Anilines 2.6. ReactionsSuch reactions with Multi have-Fuctional presented Anilines several challenges and produced inconsistencies in the outcomesSuch whenreactions more have than presented one aromatic-primary-amine several challenges isand present produced in the inconsistencies starting material. in Thethe outcomes main issue when is that more the than formation one aromatic of one dithiazole-primary-amine ring likely is present deactivates in the starting the system ma- toterial. an additionalThe main SissueEAr process.is that the One formation of the earlier of one attempts dithiazole to ring circumvent likely deactivates this was with the 1,5-diaminonaphthalenesystem to an additional S [E49Ar], process. but the actualOne of product the earlier isolated attempts12b towas circumvent not the predicted this was compoundwith 1,5-diaminonaphthalene12c (Scheme 17). Instead, [49], but the proposedthe actual structure product12b isolatedwas determined 12b was not supported the pre- bydicted the infraredcompound spectra 12c (Scheme suggesting 17). theInstead, presence the proposed of the thiosulﬁnic structure amide.12b was Quantitative determined oxidationsupported andby the sulphur infrared removal spectra bysuggesting thermolysis the presence or reaction of the with thiosulfinic NaNO3 amide.or Zn Quan- metal suggestedtitative oxidation that there and was sul onlyphur one removal thiosulﬁnic by thermolysis amide group or per reaction molecule. with However, NaNO3 or these Zn metal suggested that there was only one thiosulfinic amide group per molecule. However, these results alone do not conclusively prove the suggested structure 12b. It is interesting that the 5-membered dithiazole ring does not form as is known to happen with other naphthyl monoamines [16].

S S S S2Cl2 Cl S NH NH N H N 2 N 2 N S Cl S S 12a Cl 12c 12b Scheme 17. The product 12b obtained by Ried et al., alongside the dithiazoyl product that was not detected 12c [49].

In contrast to this example, a variety of aromatic compounds possessing two dithiazole moieties have been synthesised and characterised, although these have not been generated using the standard Herz reaction conditions [11,15]. Remarkably, there is an account of three[1,2,5]thiadiazole rings bound to benzene (13a, Figure 7) [50,51], as well as the related [1,2,3]thiadiazole (13b, Figure 7) [52]. There remains no evidence of this achievement for the benzotris[1,2,3]dithiazole equivalent (13c, Figure 7).

S N N N S N N S S N S S S N S N N N N N N S S N N S S

13a 13b 13c Figure 7. The structures of 13a) benzotris[1,2,5]thiadiazole [51], 13b) benzotris[1,2,3]thiadiazole [52] and 13c) benzotris[1,2,3]dithiazolium, for which no structure bearing these three rings is known to exist.

The presence of multiple instances of this moiety increases the reduction potential and makes these derivatives especially attractive in materials chemistry [48]. The first example of a benzo-bis[1,2,3]dithiazole (14b–d, Scheme 18) was prepared by Barclay et al. [15] by reacting diaminobenzenedithiol dihydrochloride (14a) in refluxing sulphur monochloride (having failed to form the target material starting with benzene-1,4-diamine). ReactionsR 2021eactions, 2, FOR2021 ,PEER 2, FOR REVIEW PEER REVIEW 13 13

N N NCr(0) (Toluene)Cr(0) (Toluene)2 2 N Tetrakis(dimethyl S S Tetrakis(dimethyl S S NC amino)ethylene NC NC S S amino)ethylene NC S S DMF, 2.69DMF, eV 2.69 eV CN CN CN CN 11a 11a 11b 11b

SchemeScheme 16. The 16.reduction The reduction of 6-malonitrile of 6-malonitrile-substituted-substituted benzodithiazole benzodithiazole to the radical to the anionradical [47,48] anion. [47,48].

2.6. Reactions2.6. Reactions with Multi with-Fuctional Multi-Fuctional Anilines Anilines Such reactionsSuch reactions have presented have presented several several challenges challenges and produced and produced inconsistencies inconsistencies in in the outcomesthe outcomes when more when than more one than aromatic one aromatic-primary-primary-amine- amineis present is present in the startingin the starting ma- ma- terial. Theterial. main The issue main is issue that isthe that formation the formation of one ofdithiazole one dithiazole ring likely ring deactivateslikely deactivates the the E systemsystem to an additional to an additional S Ar process. SEAr process. One of One the earlierof the earlierattempts attempts to circumvent to circumvent this was this was with 1,5with-diaminonaphthalene 1,5-diaminonaphthalene [49], but [49 the], but actual the actualproduct product isolated isolated 12b was 12b not was the not pre- the predicted compound 12c (Scheme 17). Instead, the proposed structure 12b was determined Reactions 2021, 2 dicted compound 12c (Scheme 17). Instead, the proposed structure 12b was determined187 supportedsupported by the infraredby the infrared spectra spectra suggesting suggesting the presence the presence of the thiosulfinic of the thiosulfinic amide. amide. Quan- Quan- 3 titativetitative oxidation oxidation and sul andphur sul removalphur removal by thermolysis by thermolysis or reaction or reaction with NaNO with NaNO or Zn3 or Zn metal suggestedmetal suggested that there that was there only was one only thiosulfinic one thiosulfinic amide groupamide pergroup molecule. per molecule. However, However, these resultsresultsthese resultsalone alone do alone do not not doconclusively conclusively not conclusively prove prove theprove the suggested suggested the suggested structure structure structure 12b12b. It. It12bis isinteresting. interestingIt is interesting that that thethethat 5- 5-membered memberethe 5-membered dithiazole dithiazoled dithiazole ring ring does does ring not does formform not asas form is is known known as is toknown to happen happen to withhappen with other other with naphthyl other naphthylmonoaminesnaphthyl monoamines monoamines [16 ].[16]. [16].

S S S S S S S2Cl2 Cl S NH S2Cl2 NH Cl S 2 NH NH N N N H2N H N 2 N N 2 N S Cl S Cl S S S S 12a 12a Cl 12bCl 12c 12c 12b SchemeScheme 17. The 17.product The product 12b obtained 12b obtained by Ried by et Riedal., alongside et al., alongsidealongside the dithiazoyl the dithiazoyldithiazoyl product product that was thatthat not waswas notnot detecteddetected 12c [49] 12c. [[4499]]..

In contrastIn contrastcontrast to this totoexample, this this example, example, a variety a a variety variety of aromatic of of aromatic aromatic compounds compounds compounds possessing possessing possessing two two dithia- two dithiazole dithiazole moietiesmoietieszole moieties have have been have been synthesised been synthesised synthesised and and characterised, characterised, and characterised, although although although these these have these have not nothave been been not gen- generatedbeen generated usingeratedusing thetheusing standardstandard the standard HerzHerz reactionreaction Herz reaction conditionsconditions conditions [11[11,15],15]. .[11,15] Remarkably,Remarkably,. Remarkably, therethere is is there an an account ac- is an ac- of count ofthree[1,2,5]thiadiazolecount three[1,2,5]thiadiazole of three[1,2,5]thiadiazole rings rings bound bound rings to benzeneboundto benzene to (13a benzene (,13a Figure, Figure (13a7)[, 50 Figure7), 51[50,51]], as7) well,[50,51] as well as, the as as relatedwell as the related[1,2,3]thiadiazolethe related [1,2,3]thiadiazole [1,2,3]thiadiazole (13b, Figure(13b, Figure7()[13b52, ]. Figure7 There) [52] .7 remains )There [52]. Thereremains no evidence remains no evidence of thisno evidence achievement of this of this for tris 13c achievementtheachie benzovement for the [1,2,3]dithiazole forbenzo thetris benzo[1,2,3]dithiazoletris equivalent[1,2,3]dithiazole equivalent ( , Figureequivalent (13c7)., Figure (13c, Figure7). 7).

N S N S N S N N N N S N S N N S S S S N N S S S S N S S S N N N N N N N N N N N N N N S S S S S S S N N N S

13a 13a 13b 13b 13c 13c Figure 7.Figure The structures 7. The structures of 13a) ofbenzoof (13a13atris)) benzo benzo[1,2,5]thiadiazoletristris[1,2,5]thiadiazole [51], 13b [[51]51) benzo],, (13b13btris)) benzo benzo[1,2,3]thiadiazoletristris[1,2,3]thiadiazole[1,2,3]thiadiazole [52] [[52]52] and 13cand) benzotris[1,2,3]dithiazolium, (13c13c)) benzotris[1,2,3]dithiazolium, benzotris[1,2,3]dithiazolium, for which for for no which which structure no no structure structure bearing bearing these three these rings three is ringsknown isis knownknownto toto exist. exist.

The presenceThe presencepresence of multiple ofof multiple multiple instances instances instances of this of ofmoiety this this moiety moiety increases increases increases the thereduction the reduction reduction potential potential potential and and makesmakesand makesthese these deri these derivativesvatives derivatives especially especially especially attractive attractive attractive in in materials materials in materials chemistry chemistry chemistry [48] [48.]. The The[48] first ﬁrst. The ex- example first ex- Reactions 2021, 2, FOR PEER REVIEW 14 ample ofampleof aa benzo-be ofnzo a- bisbebis[1,2,3]dithiazolenzo[1,2,3]dithiazole-bis[1,2,3]dithiazole ((14b14b––dd ,(, 14b SchemeScheme–d, Scheme 1818)) waswas 18 preparedprepared) was prepared byby BarclayBarclay by Barclay etet al. al. [ 15 et] byal. [15] byreacting[15] reacting by reacting diaminobenzenedithiol diaminobenzenedithiol diaminobenzenedithiol dihydrochloride dihydrochloride dihydrochloride (14a (14a) in) in reﬂuxing(14a refluxing) in refluxing sulphur sulphur monochloridesulphur mon- mon- ochloride(havingochloride (having failed (having failed to form tofailed form the to targetthe form target materialthe materialtarget starting material starting with starting with benzene-1,4-diamine). benzene with benzene-1,4-diamine).-1,4- Thediamine). solid Thecompound solid compound isolated was isolated radical was cation radical14b cation, which 14b can, which be either can be reduced either reduced to the neutral to the neutralcompound compound (14c) with (14c triphenylantimony) with triphenylantimony or further or further oxidised oxidised to the non-radicalto the non-radical di-cation di- cation(14d) with (14d either) with sulfuryl either sulfuryl chloride chloride or iodobenzene or iodobenzene dichloride, dichloride, but not milder but not oxidants milder suchoxi- dantsas Cl2 such(Scheme as Cl 182 ()[Scheme15]. 18) [15].

H N SH N S Ph Sb N S 2 S2Cl2(neat) 3 S S S S Reflux, 4 h S N Cl S N HS NH2 a b 14a 14b, 23% yield 14c, 49% yield PhICl Or 2, AlCl3 N SOCl Cl S 2 (solvent) S S 16 Reflux, h S N Cl 14d

Scheme 18. TheThe r resultsesults obtained by Barclay et al. in preparing benzo benzo--bis[1,2,3]dithiazolebis[1,2,3]dithiazole compoundscompounds [[15]15]..

While diaminobenzenes often do not react directly with disulfur dichloride to form the desired benzobisdithiazole, there are some notable exceptions, one being where diaminonaphthalene (15a) was reacted under the Herz reaction conditions to give the desired naphthalene-bis[1,2,3]dithiazole (15b, Scheme 19) [53]. Another exception comes from more recent literature where 2,6-diamino-1,4-dihydroxybenzene was reacted to a benzobisdithiazole product (15d, Scheme 19) [54] as had been demonstrated for a similar compound once before [55]. In these cases, the starting diamine (15a or 15c) was extremely electron-rich (and significantly more so than would be expected for an aryl-diamine), which might explain the success.

H N SbPh , MeCN, H 2 N 3 N r.t. 24 h 1. S2Cl2-DCM (3:2), r.t. 24 h Cl S S S S S 2. S Pyridine (6 equi.v) S Cl S MeCN-DCM, r.t. 2 h. NH N N 15a 2 Assumed intermediate (or 15b, 47% yield similar), Not isolated (from diamine) OH O H N NH N N 2 2 S Cl MeCN, 2 2 (9 equiv.), S S 'gentle reflux' 16 h S S .2HCl Cl OH 15c OH 15d, 80% yield Scheme 19. Two unique circumstances where two benzodithiazole moieties (15b or 15d) have formed from an aryl diamine (15a or 15c) using disulfur dichloride [53,54].

3. Applications of Benzodithiazoles as Synthetic Intermediates The uses of the Herz reaction products, from their age of discovery until today, can be divided into two categories: as synthetic intermediates towards valued cyclic structures (via heterolytic or homolytic transformations) and for their electronic/absorbance properties, previously as dyes and now in smart electronic materials. This section will focus on the derivatives of benzodithiazole compounds, which can be generated through heterolytic mechanisms, while the following section will elaborate on the access to products possible via radical-based transformations. Our final sub-section that is more forward looking will overview their applications in modern materials chemistry. There are outlined in the literature a variety of simple transformations of Herz compounds to other entities. Overviewed in this section will be their advantages and disad- vantages when applied to laboratory or commercial-scale projects. The Herz reaction itself is easy to perform in the laboratory by adding liquid disulfur dichloride dropwise to a stirred solution of aniline in acetic acid solvent (Scheme 20). Following filtration and Reactions 2021, 2, FOR PEER REVIEW 14

The solid compound isolated was radical cation 14b, which can be either reduced to the neutral compound (14c) with triphenylantimony or further oxidised to the non-radical di- cation (14d) with either sulfuryl chloride or iodobenzene dichloride, but not milder oxidants such as Cl2 (Scheme 18) [15].

H N SH N S Ph Sb N S 2 S2Cl2(neat) 3 S S S S Reflux, 4 h S N Cl S N HS NH2 a b 14a 14b, 23% yield 14c, 49% yield PhICl Or 2, AlCl3 N SOCl Cl S 2 (solvent) S S 16 Reflux, h S N Cl Reactions 2021, 2 14d 188

Scheme 18. The results obtained by Barclay et al. in preparing benzo-bis[1,2,3]dithiazole compounds [15].

While diaminobenzenes often do not react directly with disulfur dichloride to form the desired desired benzo benzobisbisdithiazole,dithiazole, there there are are some some notable notable exceptions, exceptions, one one being being where where dia- di- minonaphthaleneaminonaphthalene (15a (15a) was) was reacted reacted under under the the Herz Herz reaction reaction conditions conditions to give to give the desired the de- naphthalenesired naphthalene--bis[1,2,3]dithiazolebis[1,2,3]dithiazole (15b, Scheme (15b, Scheme 19) [53] 19.)[ Another53]. Another exception exception comes comes from morefrom morerecent recent literature literature where where2,6-diamino 2,6-diamino-1,4-dihydroxybenzene-1,4-dihydroxybenzene was reacted was reacted to a benzo- to a bisbenzodithiazolebisdithiazole product product (15d, Scheme (15d, Scheme 19) [54] 19 as)[ 54had] as been had demonstrated been demonstrated for a similar for a similar compoundcompound once once before before [55] [.55 In]. these In these cases, cases, the the starting starting diamine diamine (15a (15a oror 15c15c) )was was extremely extremely electronelectron-rich-rich (and(and signiﬁcantly significantly more more so so than than would would be expected be expected for an for aryl-diamine), an aryl-diamine), which whichmight explainmight explain the success. the success.

H N SbPh , MeCN, H 2 N 3 N r.t. 24 h 1. S2Cl2-DCM (3:2), r.t. 24 h Cl S S S S S 2. S Pyridine (6 equi.v) S Cl S MeCN-DCM, r.t. 2 h. NH N N 15a 2 Assumed intermediate (or 15b, 47% yield similar), Not isolated (from diamine) OH O H N NH N N 2 2 S Cl MeCN, 2 2 (9 equiv.), S S 'gentle reflux' 16 h S S .2HCl Cl OH 15c OH 15d, 80% yield Scheme 19. Two uniqueunique circumstancescircumstances where where two two benzodithiazole benzodithiazole moieties moieties (15b (15bor 15dor 15d) have) have formed formed from from an aryl an aryl diamine dia- (mine15a or (15a15c or) using 15c) using disulfur disulfur dichloride dichloride [53,54 ].[53,54].

3. Applications Applications of Benzodithiazoles as Synthetic Intermediates The uses of thethe HerzHerz reactionreaction products, products, from from their their age age of of discovery discovery until until today, today, can can be bedivided divided into into two two categories: categories: as syntheticas synthetic intermediates intermediates towards towards valued valued cyclic cyclic structures structures (via (viaheterolytic heterolytic or homolytic or homolytic transformations) transformations) and and for theirfor their electronic/absorbance electronic/absorbance properties, properties,previously previously as dyes as dyes and nowand now in smart in smart electronic electronic materials. materials. This This section section will will focus focus on theon thederivatives derivatives of benzodithiazole of benzodithiazole compounds, compounds, which which can can be generatedbe generated through through heterolytic hetero- lyticmechanisms, mechanisms, while while the following the following section section will will elaborate elaborate on the on accessthe access to products to products possible pos- siblevia radical-based via radical-based transformations. transformations. Our finalOur final sub-section sub-section that isthat more is more forward forward looking looking will willoverview overview their their applications applications in modern in modern materials materials chemistry. chemistry. There are outlined in the literature a variety of simple transformations of of Herz com- com- pounds to to other other entities. entities. Overviewed Overviewed in in this this section section will will be be their their advantages advantages and and disad- dis- vantagesadvantages when when applied applied to laboratory to laboratory or commercial or commercial-scale-scale projects. projects. The Herz The Herzreaction reaction itself isitself easy is to easy perform to perform in the in laboratory the laboratory by adding by adding liquid liquid disulfur disulfur dichloride dichloride dropwise dropwise to a stirredto a stirred solution solution of aniline of aniline in inacetic acetic acid acid solvent solvent (Scheme (Scheme 20 20).). Following Following filtration filtration and washing of the generated precipitate with organic solvents, the product salt is collected, and although it has been separated from organic by-products, such as chloroanilines, significant contamination of elemental sulphur is typically also collected. While some clearly very toxic reagents are employed, and measures are needed to mitigate the HCl fumes that are generated. The reaction uses mild conditions, sustainable solvents and very affordable reagents (disulfur dichloride, CAS 10025-67-9, Aldrich price dated May 2021; 1 kg £34.80). Literature yields range from low, 30% to much higher, 80%, as vastly different synthesis methods and purifications are used. In some cases, it is possible the reported yield includes some contamination by elemental sulphur (which could go undetected by general methods of NMR spectroscopy and MS). Overall, the yield is non-quantitative because of side processes that produce compounds such as 4-chloroaniline, azobenzenes and sulphur-phenyl-diimides [4,33,37], although these are readily removed from the product by washing with a non-polar solvent such as toluene (as the Herz salt is insoluble). The Herz chloride salt itself remains very difficult to purify further, and this is generally achieved by performing an ion exchange with the installation of a larger counter-anion to form a salt with greater solubility, followed by recrystallisation [4]. Reactions 2021, 2, FOR PEER REVIEW 15 Reactions 2021, 2, FOR PEER REVIEW 15

washing of the generated precipitate with organic solvents, the product salt is collected, andwashing although of the it hasgenerated been separated precipitate from with organic organic by -solventsproducts, the, such product as chloroanilines salt is collected, sig-, nificantand although contamination it has been of separatedelemental sulphurfrom organic is typically by-products also collected., such as Whilechloroanilines some clearly, sig- verynificant toxic contamination reagents are ofemployed elemental, and sulphur measures is typically are needed also collected. to mitigate While the some HCl clearlyfumes thatvery are toxic generated reagents. Tarehe reactionemployed uses, and mild measures conditions, are needed sustainable to mitigate solvents the and HCl very fumes af- fordablethat are generatedreagents (.d Tisulfurhe reaction dichloride, uses mildCAS conditions,10025-67-9, sustaiAldrichnable price solvents dated Mayand very2021; af- 1 kgfordable £34.80). reagents Literature (disulfur yields dichloride,range from CASlow, 30%10025 to-67 much-9, Aldrich higher, price 80%, datedas vastly May different 2021; 1 synthesiskg £34.80). methods Literature and yields purifications range from are low, used. 30% In toso muchme cases, higher, it is 80%, possible as vastly the reporteddifferent yieldsynthesis includes methods some and contamination purifications by are elemental used. In sulphur some cases, (which it couldis possible go undetected the reported by generalyield includes methods some of NMRcontamination spectroscopy by elemental and MS). sulphur Overall (which, the yield could is gonon undetected-quantitative by becausegeneral ofmethods side processes of NMR that spectroscopy produce compounds and MS). Overallsuch as, 4the-chloroaniline, yield is non azobenzenes-quantitative andbecause sulphur of side-phenyl processes-diimides that produce[4,33,37] ,compounds although these such areas 4 -readilychloroaniline, removed azobenzenes from the productand sulphur by washing-phenyl -withdiimides a non [4,33,37]-polar solvent, although such theseas toluene are readily(as the Herzremoved salt isfrom insolu- the ble).product The byHerz washing chloride with salt a itselfnon- polarremains solvent very suchdifficult as toluene to purify (as further the Herz, and salt this is isinsolu- gen- Reactions 2021, 2 erallyble). The achieved Herz chlorby performingide salt itself an remains ion exchange very difficult with the to installation purify further of a, andlarger this counter is gen-189- anionerally toachieved form a saltby performingwith greater an solubility, ion exchange followed with by the recrystallisation installation of [4]a larger. counter- anion to form a salt with greater solubility, followed by recrystallisation [4]. NH2 AcOH N NH2 NS + 3 AcOH S2Cl2 r.t. 4 h S SCl +4 S + 4 HCl + 3 S Cl Cl Cl +4 S + 4 HCl 2 2 r.t. 4 h Cl 2 S 1 2 1

Scheme 20. The very general procedure for the first stage of the Herz reaction. SchemeScheme 20.20. The very general procedureprocedure forfor thethe firstfirst stagestage ofof thethe HerzHerz reaction.reaction. While well-suited for a small-scale preparation, limitations regarding process chem- WhileWhile well-suitedwell-suited for a small-scalesmall-scale preparation, limitations regarding process chemistry include thethe super-stoichiometricsuper-stoichiometric amount amount of of disulfur disulfur dichloride dichloride that that is is often often used used (5 or(5 istry include the super-stoichiometric amount of disulfur dichloride that is often used (5 ormore more equivalents), equivalents), along along with with the the seemingly seemingly inevitable inevitable chlorination chlorination ofof thethe parapara carbon or more equivalents), along with the seemingly inevitable chlorination of the para carbon relative to the amino group (see Scheme 10). This is without considering the problematic relative to the amino group (see Scheme 10). This is without considering the problematic disposal of the cocktail of chloro chloro-aromatic-aromatic compounds (several being classed as persistent disposal of the cocktail of chloro-aromatic compounds (several being classed as persistent organic pollutants pollutants—POPs)—POPs) that are found in the filtrate filtrate when filtering filtering the Herz salts from organic pollutants—POPs) that are found in the filtrate when filtering the Herz salts from the reaction reaction mixture mixture and and washing. washing. Thus, Thus, due due to tothe the low low characteristic characteristic yields yields and andproblem- prob- the reaction mixture and washing. Thus, due to the low characteristic yields and problem- aticlematic purifica purification,tion, designing designing routes routes for commercial for commercial application application would would be challenging, be challenging, even atic purification, designing routes for commercial application would be challenging, even ifeven the ifstarting the starting materials materials are very are veryaffordable. affordable. Furthermore Furthermore,, the reactions the reactions are somewhat are somewhat ex- if the starting materials are very affordable. Furthermore, the reactions are somewhat ex- othermicexothermic with with disulfur disulfur dichloride, dichloride, although although not notto the to theextent extent of being of being a cause a cause for concern for con- othermic with disulfur dichloride, although not to the extent of being a cause for concern ifcern properly if properly managed, managed, and could and could be readily be readily controlled controlled,, for example for example,, in a continuous in a continuous flow if properly managed, and could be readily controlled, for example, in a continuous flow systemflow system [56]. However, [56]. However, to date to, the date, application the application of the Herz of the reaction Herz reaction for bulk for chemical bulk chemi- pro- ductioncalsystem production [remains56]. However, remains a major to a majordatechallenge,, the challenge, application especially especially of with the Herz withregards reaction regards to purification tofor purification, bulk chemical, which which pro-un- doubtedlyundoubtedlyduction remains restricts restricts a themajor the utilisation utilisationchallenge, of these of especially these privileged privileged with chemical regards chemical entities.to entities.purification , which un- doubtedly restricts the utilisation of these privileged chemical entities. 3.1. Synthesi Synthesiss of Aminothiophenols 3.1. Synthesis of Aminothiophenols One of of the the simplest simplest transformations transformations of of the the Herz Herz product product is isin inthe the preparation preparation of of2- aminothiophenol2-aminothiophenolOne of the simplest compounds compounds transformations (e.g. (e.g.,, 3d,3d Scheme, Schemeof the 21 Herz). 21 Consequently,). product Consequently, is in this the thisapproach preparation approach was of wasfur- 2- therfurtheraminothiophenol patented patented [57] [ 57compoundsby] byHerz Herz within within(e.g. a, year3d a, year Scheme of the of theoriginal 21 original). Consequently, ‘Herz ‘Herz reaction’ reaction’ this patentapproach patent [18] [was18. ]. further patented [57] by Herz within a year of the original ‘Herz reaction’ patent [18]. H NH2 NH H2O N H O NH2 S O 2 + Na2SO3 + H2O NaOH S S O (3 equiv.) + Na2SO3 + H2O Cl NaOH Cl SNa Cl 3 S (3 equiv.) Cl 3d SNa 3 3d

Scheme 21. The ring-openingring-opening ofof neutral neutral Herz Herz compounds compounds to to form form the the respective respective 2-aminothiophenols. 2-aminothiophenols.Scheme 21. The ring-opening of neutral Herz compounds to form the respective 2-aminothiophenols. This hydrolysis (Scheme 21) also appears in several later publications, and while the conditions may not have been optimised or fully investigated, the process was favoured at This hydrolysis (Scheme 21) also appears in several later publications, and while the the time as a means to rapidly synthesise 2-aminothiophenols on moderate scales for other conditionsThis hydrolysis may not have (Scheme been 21 optimised) also appears or fully in severalinvestigated, later publications the process, wasand favouredwhile the projects [19]. The procedure works best when applied towards ortho aminonaphthalene- atconditions the time mayas a meansnot have to beenrapidly optimised synthesise or fully2-aminothiophenols investigated, the on process moderate was scalesfavoured for thiols,at the time as the as selectivity a means to and rapidly isolated synthesise yields are 2-aminothiophenols seemingly higher [on13 ,moderate16,58,59]. Yieldsscales for as high as 84% for the benzodithiazole formation and 90% for the ﬁnal hydrolysis have been reported at a moderate (70 g) scale of 2-aminonaphthalene-1-thiol [60]. Today, aminothiophenols are generally available and affordable to buy for small-to-medium-scale laboratory projects [61]. However, from a process perspective, they are still valued targets. Of- ten released from benzothiazole derivatives by hydrolysis, the source is atom inefﬁcient, and the removal of the C2 carbon requires a lot of energy, so there is an opportunity for improvement [62,63]. An alternative legacy method is using the Zinin reduction of 2-nitrochlorobenzene [64–67], although the reported yields for this process are generally modest at best, and there appears to have been little investigation into this process in recent times. While the formation of the ring-opened aminothiophenol from the benzodithiazole (Scheme 21) is also incredibly simple, it is also the limitations of average yields and product contamination with, e.g., sulphur residues that are problematic.

3.2. Formation of Benzothiazoles There are two interesting reports of reacting the benzodithiazole products of the Herz reaction to make benzothiazoles while avoiding the ﬁnal ring-opening step with sodium hydroxide (as a segregated step) [13,21]. The ﬁrst originates from Sawhney et al., Reactions 2021, 2 190

where the hydrolysed Herz salt is reacted with either benzoyl chloride, benzaldehyde

or even benzoic acid in a mildly basic medium. The phenyl-substituted products shown (16a–d, Table1) were synthesised. The mechanism for the ring-opening of the intermediate ReviewReview dithiazole S-oxide to form the ﬁnal products could either be due to high-temperature hydrolysis or potentially a cheletropic cyclo-elimination process. The two intermediates Benzo[1,2,3]dithiazoleBenzo[1,2,3]dithiazolewill have different Compounds:Compounds: oxidation levels depending AA HistoryHistory on whether ofof theSynthesisSynthesis reagent is the aldehyde and or the acid/acid chloride, but the reaction conditions are capable of facilitating an auto- TheirTheir Renewed Renewed ApplicabilityoxidationApplicability regarding the aldehyde inin MaterialsMaterials (in fact, the yields andand were SyntheticSynthetic often higher when using the Chemistry, Originatingaldehyde). The from scope of the the process Herz was tested Reaction only on 2-phenyl-substituted benzothiazoles, Chemistry, Originatingalthough we ourselves from have the experimentally Herz Reaction found the scope to also include 2-unsubstituted benzothiazoles [68]. Finally, as for all Herz processes, the product will have an additional

AlexanderAlexander J. J. Nicholls Nicholls* *and and Ian Ianaromatic R. R. Baxendale Baxendale chloro group present, which might require removal.

TableTable 1. 1. The The synthesis synthesis of of 2-phenylbenzothiazoles2 2-phenylbenzothiazoles-phenylbenzothiazoles byby thethe HerzHerz reactionreaction [[21][21]21]...

aa SynthesisedaSynthesised Synthesised from from from ‘method ‘method ‘method A’. A’.b A’.Synthesised b bSynthesised Synthesised from from ‘methodfrom ‘method ‘method B’. c Synthesised B’.B’. cc Synthesised Synthesised from ‘method fromfrom C’. ‘method‘method Percentages C’. Per- refer centagestocentages pure isolated refer refer to yields. to pure pure isolated isolated yields. yields.

Table3.3.Table Formation 2. 2. The The synthesis synthesis of Secondary of of 2 2-aminobenzothiazoles-aminobenzothiazoles 2-Aminobenzothiazoles from from Herz Herz compoundscompounds (e.g.(e.g.,, 99)) [13][13].. Specific 2-amine-substituted benzothiazoles can be generated by the reaction of the intermediate dithiazole S-oxide compound with isocyanides (Table2)[ 13]. These entities are incredibly valued in the discovery of new APIs but are often non-trivial to synthesise. As such, an optimised reaction sequence would be invaluable to both a medicinal hit-to-lead process and the scaled preparation, offering advantages over similar preparations [69,70]. In total, fourteen different benzothiazole-secondary amines (18a–n) have been generated from five different benzo-1,2,3-dithiazole 2-oxides (17a–e, Table2); the yield varied widely, with some being as low as 8%, though there is no indication that the process was optimised. This publication appears to be the first consideration of reacting Herz salts with a nucleophile (other than water) at the 2-position. The mechanism uses an iodine catalyst to activate the dithiazole ring so that the isocyanide can insert into the weak S–S bond. However, the precise function of the I2 was not fully elucidated. When heating was performed employing microwave radiation in the experiments [13], the rate of formation was faster, but the yield decreased. The substrate range remains good and demonstrates the possibility of installing a library of amine functionalities (derived from readily available commercial isocyanides). As an aside, the reported yields for two of the Herz compounds were surprisingly high. However, the characterisation data provided does not confirm that these samples are free of contamination from elemental sulphur, which may also impact the yield in the subsequent derivation reaction. The moderate-to-high yields for some of the final compounds are particularly encouraging, considering the Herz compound intermediates are collected

Reactions 2021, 2, Firstpage–Lastpage. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/reactions Reactions 2021, 2, Firstpage–Lastpage. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/reactions Reactions 2021, 2 191

Review by filtration and then reacted crude without any purification. It is likely that further optimisations could enhance the final yields. In addition, from a scale-up perspective, all Benzo[1,2,3]dithiazoleof the reagents Compounds: used are affordable, and A with History the exception of of Synthesis the disulfur dichloride, and are employed in minimum/catalytic quantities (the ratio of Herz compound to isocyanide Their Renewed reagentApplicability is 1:1). For this publication, in Materials the compounds and were Synthetic isolated by chromatography, although recrystallisation is likely to be an efficient purification method at larger scales, Chemistry, Originatinggiven the established from behaviour the Herz of these larger Reaction benzothiazoyl-amines [71–73]. Alternatively, it should be noted that these simple entities could instead be synthesised Alexander J. Nicholls * and Ianby R. reacting Baxendale the primary 2-aminobenzothiazole derivative with an electrophilic reagent or an aromatic cross-coupling. However, for targets where these methods are not suitable, this Tablereaction 1. The does synthesis offer access of 2-phenylbenzothiazoles to these valued targets by the in Herz two reaction relatively [21] simple. chemical steps (isocyanide formation, then substitution with Herz compound). The issue surrounding para chlorination is surprisingly resolved by the coincidence that many such APIs include an existing substituent at this position (often to increase lipophilicity and solubility).

3.4. Formation of 2-Mercaptobenzothiazoles There are a few reports of the 1,2,3-dithiazole compounds reacting with carbon disulphide to form 2-mercaptobenzothiazoles (Scheme 22)[74,75]. The reason for the rarity of such transformation reports might be that these structures are readily available from the industrial process: heating aniline with sulphur and carbon disulphide at high tem- peratures [68]. This alternative reaction of the Herz compound (Scheme 22) is unlikely to Reactions 2021, 2, FOR PEER REVIEW 19 compete with such a well-established process, although the reported yield is very high considering the product was ‘recrystallised twice’ [75].

H H N N CS2 S O S H O/NaOH Ph S 2 Ph S 19a 19b, 87% a Synthesised from ‘method A’. b Synthesised from ‘method B’. c Synthesised from ‘method C’. Per- Schemecentages 22.refer AA tosinglesingle pure reported reisolatedportedreaction yields.reaction of of a Herza Herz compound compound forming forming a 2-mercaptobenzothiazole a 2-mercaptobenzothiazole [75]. [75]. Table 2.2. The synthesis of 2-aminobenzothiazoles2-aminobenzothiazoles fromfrom HerzHerz compoundscompounds (e.g.,(e.g., 99)[) [13]13].. 3.5. Nucleophilic Aromatic Substitution Anilines (including the ring-open 2-aminothiophenol) are electron-rich aromatic systems; the π-donor effects from the amine make them perfect for electrophilic aromatic substitution but normally are inert to nucleophilic attack. Noting that some substituents to the ring were replaced by chloride during the Herz reaction, Herz proposed the possibility that the same could be done with other nucleophiles. A range of aromatic amines was reported to react with the Herz thiazolium salts (e.g., 2), displacing the chloride introduced during the Herz reaction to form a biaryl aniline product (Scheme 23) [76]. The extent to which the dithiazolium moiety activates the opposite C–Cl bond to substitution is remarkable, as the scope includes arylamines (which can be poor nucleophiles) to displace the chloride [77]. However, more surprising, Herz salts based on the more electron- rich naphthalenes can also undergo nucleophilic substitution [78]. The full experimental details and product yields are not easily realised from the patent literature; however, the reaction is described as occurring at ambient temperature, requiring two equivalents of the aniline (one as nucleophile, the other as a base) and taking a ‘very long time’ to complete. The reactions were performed in a medium of acetic acid, and the products were isolated by filtration and, in many cases, were crystalline. Interestingly, this makes it comparable to the general conditions used in the Herz reaction (e.g., Scheme 20), and hence, such substitution could probably occur as a side-process. However, the shorter reaction time and the excess of sulphur monochloride used in the Herz reaction likely favour complete consumption of aniline to the thiadiazolium rather than the insertion of the aniline into the product. As noted, the specific identities of the compounds made and their yields are not reported numerically, instead of being described as ‘good.’ The products were derivatised to the ring-opened aminothiophenols (as per previous instances where proof Reactions 2021, 2, Firstpage–Lastpage.of https://doi.org/10.3390/xxxxx structure was not possible on the original products) to aid withwww.mdpi.com/journal/ the characterisationreactions of structures.

NHR'' R' N 2 R' N Cl Cl R S R S AcOH r.t. 'very long time' S Cl S N R'' R' = H, Me, OH, 3-NO2 Yields not reported R = H, Me, naphthyl napthyl, anthraquinone, etc. R'' = aryl H, alkyl, Scheme 23. The reported scheme for the displacement of the 6-chloro of Herz salts with a primary arylamine. [76].

This substitution process was later confirmed by Strelets et al., who also discovered that the 4-methoxy substituent could also function as a leaving group in displacement reactions, albeit at one-eighth of the rate of the chloride (Scheme 24) [78]. This is noteworthy because, while OMe is an acceptable leaving group, it is such an effective π-donor substituent that it typically renders most aromatic systems impervious to any nucleophilic substance. Another interesting finding was that the displacement of one such leaving group with aniline prevented the addition of a second aniline if there were additional leaving groups present. This is consistent with the knowledge that these π-donor substituents would repel incoming nucleophiles, even more so than the methoxy. Reactions 2021, 2 192

Reactions 2021, 2, FOR PEER REVIEW 2

Table 2. Cont.

PercentagesPercentages refer refer to pure to pure isolated isolated yields. yields.

3.5.Table Nucleophilic 3. The general Aromatic scheme Substitution and isolated malononitrile adduct products from the study by Kouten- tis [40]Anilines. (including the ring-open 2-aminothiophenol) are electron-rich aromatic systems; the π-donor effects from the amine make them perfect for electrophilic aromatic substitution but normally are inert to nucleophilic attack. Noting that some substituents to the ring were replaced by chloride during the Herz reaction, Herz proposed the possibility that the same could be done with other nucleophiles. A range of aromatic amines was reported to react with the Herz thiazolium salts (e.g., 2), displacing the chloride introduced during the Herz reaction to form a biaryl aniline product (Scheme 23)[76]. The extent to which the dithiazolium moiety activates the opposite C–Cl bond to substitution is remarkable, as the scope includes arylamines (which can be poor nucleophiles) to displace the chloride [77]. However, more surprising, Herz salts based on the more electron-rich naphthalenes can also undergo nucleophilic substitution [78]. The full experimental details and product yields are not easily realised from the patent literature; however, the reaction is described as occurring at ambient temperature, requiring two equivalents of the aniline (one as nucleophile, the other as a base) and taking a ‘very long time’ to complete. The reactions were performed in a medium of acetic acid, and the products were isolated by Reactions 2021, 2, FOR PEER REVIEW 19

H H N N CS2 S O S H O/NaOH Ph S 2 Ph S 19a 19b, 87%

Scheme 22. A single reported reaction of a Herz compound forming a 2-mercaptobenzothiazole [75].

3.5. Nucleophilic Aromatic Substitution Anilines (including the ring-open 2-aminothiophenol) are electron-rich aromatic systems; the π-donor effects from the amine make them perfect for electrophilic aromatic substitution but normally are inert to nucleophilic attack. Noting that some substituents to the ring were replaced by chloride during the Herz reaction, Herz proposed the possibility that the same could be done with other nucleophiles. A range of aromatic amines was reported to react with the Herz thiazolium salts (e.g., 2), displacing the chloride introduced during the Herz reaction to form a biaryl aniline product (Scheme 23) [76]. The extent to which the dithiazolium moiety activates the opposite C–Cl bond to substitution is remarkable, as the scope includes arylamines (which can be poor nucleophiles) to displace the chloride [77]. However, more surprising, Herz salts based on the more electron- rich naphthalenes can also undergo nucleophilic substitution [78]. The full experimental details and product yields are not easily realised from the patent literature; however, the reaction is described as occurring at ambient temperature, requiring two equivalents of Reactions 2021, 2 193 the aniline (one as nucleophile, the other as a base) and taking a ‘very long time’ to complete. The reactions were performed in a medium of acetic acid, and the products were isolated by filtration and, in many cases, were crystalline. Interestingly, this makes it com- parableﬁltration to and, the ingeneral many cases,conditions were used crystalline. in the Interestingly,Herz reaction this (e.g. makes, Scheme it comparable 20), and hence to the, suchgeneral substitution conditions could used inprobably the Herz occur reaction as a (e.g., side Scheme-process. 20 However,), and hence, the such shorter substitution reaction timecould and probably the excess occur of assulphur a side-process. monochloride However, used the in the shorter Herz reaction reaction time likely and favour the excess com- pleteof sulphur consumption monochloride of aniline used to inthe the thiadiazolium Herz reaction rath likelyer than favour the completeinsertion consumptionof the aniline intoof aniline the product. to the thiadiazoliumAs noted, the specific rather thanidentities the insertion of the compounds of the aniline made into and the their product. yields Asare noted,not reported the speciﬁc numerically, identities instead of the compounds of being described made and as their‘good yields.’ The are products not reported were derivatisednumerically, to instead the ring of-opened being described aminothioph as ‘good.’enols (as The per products previous were instances derivatised where toproof the ofring-opened structure was aminothiophenols not possible on (as the per original previous products) instances to where aid with proof the of characterisation structure was not of possiblestructures. on the original products) to aid with the characterisation of structures.

This substitution process was later conﬁrmedconfirmed by Strelets et al.,al., who also discovereddiscovered that the 4-methoxy4-methoxy substituent could also function as a leavingleaving groupgroup inin displacementdisplacement reactions, albeit at one one-eighth-eighth of the rate of the chloride ( (SchemeScheme 24))[ [78]78].. This This is is notewor- notewor- thy because, while OMe is an acceptable leaving group, it is such an effective π-donor-donor substituent that it ty typicallypically renders most aromatic systems impervious to any nucleophilic substance. AnotherAnother interestinginteresting ﬁnding finding was was that that the displacementthe displacement of one of such one leavingsuch leaving group withgroup aniline with aniline prevented prevented the addition the addition of a second of a anilinesecond ifaniline there wereif there additional were additional leaving Reactions 2021, 2, FOR PEER REVIEWgroups present. This is consistent with the knowledge that these π-donor substituents20 leaving groups present. This is consistent with the knowledge that these π-donor substit- woulduents would repel incomingrepel incoming nucleophiles, nucleophiles even, more even somore than so the than methoxy. the methoxy.

NH2 N N Cl Cl S S S Cl S AcOH r.t. 24 h N 21a H Rate constant (k) = (1.58 ± 22a 71% − − − , yield 0.04) x 10 2 L s 1 mol 1

NH2 N N Cl Cl S S S AcOH r.t. 24 h N S MeO H 21b Rate constant (k) = (1.24 ± − − − 22b, 76% yield 0.03) x 10 3 L s 1 mol 1

SchemeScheme 24.24. TheThe measuredmeasured raterate constants,constants, comparingcomparing thethe raterate ofof S SNNArAr ofof thethe chloridechloride substituentsubstituent versusversus thethe methoxymethoxy inin thethe otherwiseotherwise equivalent equivalent structure structure [ 78[78]]. .

TheThe scopescope of of SN SArNAr reactions reactions with with Herz Herz salts salts was expandedwas expanded upon byupon Koutentis by Koutentis et al. [40 et] andal.[40] more and recently more recently applied applied in research in research by Makarov by Makarov [47] and [47] Chulanova and Chulanova [45]. Although [45]. Alt- therehough were there some were difﬁculties some difficulties in the preparations in the preparations of particular of particular Herz salts, Herz the salts, intermediates the inter- thatmediates could that be isolated could be in highisolated purity in werehigh purity reacted were successfully reacted withsuccessfully malononitrile with malono- to form thenitrile target to form adducts the target in low-to-mid adducts yieldsin low- (Tableto-mid3). yields In each (Table case, 3). the In producteach case was, the isolated product bywas chromatography, isolated by chromatography, although the although reactions the were reactions generally were unselective generally andunselective a lot of and by- productsa lot of by were-products detected were in detected the reaction in the mixture, reaction including mixture, including 2-cyanobenzothiazoles, 2-cyanobenzothia- the oxidisedzoles, the ‘sulfone’ oxidised form ‘sulfone’ of the form Herz of startingthe Herz materials starting materials and even and evidence even ofevidence thiocyanate- of thi- insertionocyanate into-insertion the aromatic into the system. aromatic system. −

Table 3. The general scheme and isolated malononitrile adduct products from the study by Kouten- tis [40].

1 R R1 R1 S Cl , AcOH R2 NH 2 2 R2 Cl 2 2 90 °C, 8 h N NC CN R N S S i NC H H Cl S EtN Pr2 (2 equiv.) S 3 3 DCM, 20 °C, 1 h R R CN R3 23a-j

N N N S S S NC NC S S NC S CN CN CN a 23a, 11% 23b, 16% 23c, <5%

OMe N MeO S N N NC S S S NC NC S S CN a CN CN 23d, <5% 23e, 11% 23f, 14%

N N S S N NC NC S S S NC S CN CN 23g, 13% 23h, 15% CN 23i, 40% S N N N S NC S CN 23j, 30% Percentages refer to pure isolated compounds. Reactions 2021, 2, FOR PEER REVIEW 2

Reactions 2021, 2 194

Percentages refer to pure isolated yields.

TableTable 3. 3. The general general scheme scheme and and isolated isolated malononitrile malononitrile adduct adduct products products from the fromstudy theby Kouten- study by Koutentistis [40]. [40].

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Reactions 2021, 2, FOR PEER REVIEW 21

PercentagesPercentages refer refer to pure to pure isolated isolated compounds. compounds. 3.6. Future Applicablity in Synthesis 3.6.Table Future 4. Five Applicablity different solids in Synthesis based on the benzo[1,2,3]dithiazole moiety and their measured con- ductivitiesMany atpublications room temperature describing [53,98] .the reaction of Herz 1,2,3-dithiazole compounds to otherMany simple publications structures are describing academically the reaction noteworthy of Herz; however 1,2,3-dithiazole, they are compounds not utilised to com- other −1 simplemercially. structuresSolid The issues Formula are academicallyoutlined simplyMeasured noteworthy; outweigh Conductivity however,any value/ theyS added cm are ( Oneto not the utilisedSignificant raw materials commercially. Figure, and) Thehence issues, such outlined small targets simply are outweigh generally any made value using added well to-established the raw materials, pathways and [77] hence,. To suchspeculate small whether targets arethe generallyHerz reaction made could using have well-established possible future pathways applicability, [77]. Toall speculatethree of whetherthe key transformations the Herz reaction (Figure could 8) havethat occur possible as part future of the applicability, process must all be three considered of the keyin 10−5 transformationstandem. (Figure8) that occur as part of the process must be considered in tandem.

28a • Regioselective and protected introduc- NH2 N tion of 1,2-Nitrogen-Sulphur moiety. S2Cl2 S Cl • Regioselective introduction of chloride AcOH Cl S to para position of aniline as a scaffold 1 2 for substitution,10−2 or otherwise. • Activation of the structure to SNAr.

Figure 8. The three transformations that occur simultaneously in the Herz reaction. The three28b transformations that occur simultaneously in the Herz reaction. With thesethese threethree transformationstransformations (Figure(Figure8 )8 in) in mind, mind, there there is is potential potential to to reach reach complex com- APIplex structuresAPI structures (Figure (Figure9) in 9 relatively) in relatively few steps,few steps, from from simple simple anilines. anilines. For For example, example, the benzothiazolethe benzothiazole component component of antidepressantof antidepressant ‘E2011’ ‘E201 could1′ could be be retro-synthesised retro-synthesised from from the 10−5 1,2,3-dithiazoliumthe 1,2,3-dithiazolium and and the the simple simple carboxylic carboxylic acid acid shown. shown. Additionally, Additionally, the the aromatic aromatic chloride introduced introduced in in the the Herz Herz reaction reaction could could act actas a as scaffold a scaffold for coup for couplingling with withthe ox- the oxazolidinoneazolidinone shown shown28c (Figure (Figure 9)9 )and and the the electron electron-withdrawing-withdrawing dithiazolium dithiazolium ring ring enabling enabling thethe nucleophilic attack, attack, adding adding the the left left-hand-side-hand-side functionality functionality with with ease. ease. Four Four further further ex-

amples are proposed, where a complex API is retro-synthesised back to simple building blocks by considering the Herz reaction. Reactions 2021, 2 195

Reactions 2021, 2, FOR PEER REVIEWexamples are proposed, where a complex API is retro-synthesised back to simple building22

blocks by considering the Herz reaction.

N N O S CN MeO + MeO S HO CN N S OH N Cl OH O O O O 'E2011' Antidepressant, [79] other medicinal [80]

MeO N NH2 NH + S + S2Cl2 O Cl S Cl O 2 1

O O N O S O N S NH N Cl + N N S H H

Ceramide Kinase Inhibitor, [81] O N NH2 + S + S2Cl2 NH2 S Cl 2 Cl 1

H O H O N O N O N S N S

N N O S + S S Cl N N H H NH NH O O Fibrosis & other Inflammation Inhibitor, [83]

O O O O S S HN HN + S2Cl2 N N N N O NH O N 2 S NH Self-Reaction NH2 S Cl 2 Cl Protection-Strategy

O N O O O N CF3 S NH S CF S N S Cl 3 N S H N H + H2N H2N NAE (Nedd8 Activating Enzyme) Inhibitor, [82] O S N + NH2 NH2 S + S2Cl2 S Cl 2 Cl 1 H2N

HN O HN N NH O O O N NH O HN S S O NC O S S O N O H CN Endothelia Lipase Inhibitor [84] HN N N Cl O S + S CN NH2 NC O NH O S Cl NC S Cl 2 + + 1 S2Cl2 CN HO S O O FigureFigure 9. Five 9. Five different different conﬁrmed confirmed APIs APIs and and theirtheir theoreticaltheoretical retro retro-synthesis-synthesis using using the the Herz Herz reaction reaction [79– [7985]–.85 ]. ReactionsRReactionseactions 20212021,, 22,, FORFOR PEERPEER REVIEWREVIEW 1962323

4.4. ApplicationApplication ofof the the Herz Herz Radicals Radicals as as Synthetic Synthetic Intermediates Intermediates InIn addition additionaddition to toto the the scoresscores ofof materials-basedmaterialsmaterials--basedbased applications,applications, the the ‘Herz ‘Herz radicals’radicals’ have have foundfound synthetic synthetic value value as asas intermediates intermediatesintermediates towards towards other other unique unique compounds.compounds. In In comparison comparison toto thethe heterolyticheterolytic processes processes outlined outlined in in t thethehe previousprevious sections, sections, the the correspondingcorresponding homolytic processesprocesses have have not not been been as as widely widely investigated investigated,investigated,, and and the the isolated isolated yields yields are are not not always always as as high.high. TheThe benzodithiazoyl benzodithiazoyl radicalradical nonethelessnonetheless providesprovides entryentry to to some some highly highly novel novel andand complexcomplex systems, systems, many many with with few few or or no no known known alternative alternative formation formation procedures.procedures.

4.1.4.1. ReactionReaction withwith MolecularMolecular Oxygen Oxygen ItIt has has become become known known due due to to stability stability issues issues that that some some Herz Herz radicals radicalsradicals could could react react with with molecular O2 to form new products, though this had not been utilised deliberately to molecularmolecular OO22 toto formform newnew products,products, thoughthough thisthis hadhad notnot beenbeen utilisedutilised deliberatelydeliberately toto trytry andtryand and identifyidentify identify thethe theproductsproducts products untiluntil until anan aninvestigationinvestigation investigation byby byMakarovMakarov Makarov etet al. etal. al. [86][86] [86.. Interestingly,].Interestingly, Interestingly, aa disulphideadisulphide disulphide derivativederivative derivative ((24c24c (24c)) waswas) was isolatedisolated isolated inin decentdecent in decent yieldyield yield(60%)(60%) (60%) byby reactingreacting by reacting thethe HerzHerz the radicalradical Herz shradicalshownown (( shown24b24b,, SchemeScheme (24b, Scheme 2525)) withwith 25 molecularmolecular) with molecular oxygenoxygen oxygen inin solution.solution. in solution. ThisThis appearsappears This appears toto bebe aa tostandstand be a-- alonestand-alonealone example,example, example, withwith nono with recordsrecords no records ofof similarsimilar of similar compoundscompounds compounds oror derivatives.derivatives. or derivatives.

i iPrPr i i SS iPrPr iPrPr OO NN Ph Sb NN Ph33Sb NN OO2 ii 2 PrPr SS i SS SS SS iPrPr benzenebenzene iiPr SS iiPr SS Pr ClCl Pr N O 24a24a 24b24b N O i SS iPrPr 24c24c,, 60%60% yield yield SchemeScheme 25. 25. TheThe synthesis synthesis of of a a new new compound compound identified identiﬁedidentified byby MarakovMarakov etet al.al. [[86][86]86]...

4.2.4.2. SynthesisSynthesis ofof PhenazinesPhenazines Phenazines,Phenazines, whowho whosesese compound compound class class includes includes high high-valuedhigh--valuedvalued redox redox-activeredox--activeactive structures structures,structures,, suchsuch as as pyocyanin pyocyanin [87] [[87]87],,, are self self-condensationself--condensationcondensation products of of the the reaction reaction of of benzodithiazoyl benzodithiazoyl radicals.radicals. These These desirabledesirable structuresstructuresstructures have havehave numerous numerousnumerous issues issuesissues in inin their theirtheir supply supplysupply chains chainschains [88 [88[88–90––],90]90] so,, soalternativeso alternativealternative syntheses synthesessyntheses are are frequentlyare frequentlyfrequently considered. considered.considered. While WhileWhile the formation thethe formationformation of phenazines ofof phenazinesphenazines from fromradicalisedfrom radicalisedradicalisedN- and NNS---containing andand SS--containingcontaining aromatics aromaticsaromatics was not novelwaswas not [not91], novelnovel an entirely [91][91],, newanan entirelyentirely method newnew was methoddiscoveredmethod waswas by discovereddiscovered Mayer in 1985 byby MayerMayer when heating inin 19851985 the whenwhen Herz heatingheating radical thethe generated HerzHerz radicalradical from 3generatedgeneratedH-naphtho[2,1- fromfrom 3d3H][1,2,3]dithiazoleH--naphtho[2,1naphtho[2,1--dd][1,2,3]dithiazole][1,2,3]dithiazole 2-oxide (25a, Scheme 22--oxideoxide 26 ((25a),25a forming,, SchemeScheme the 2626 target),), formingforming phenazine thethe targettarget (25d phenazinephenazine) in high (yield(25d25d)) inin [33 highhigh]. This yieldyield outstanding [33][33].. ThisThis outstandingoutstanding transformation transformationtransformation was further waswas reasoned furtherfurther reasonedreasoned mechanistically mechanis-mechanis- by ticallyRawsontically byby [ 4 RawsonRawson], though [4][4] there,, thoughthough are no ththere furtherere areare no experimentalno furtherfurther experimentalexperimental reports of its reportsreports use nor ofof any itsits useuse evidence nornor anyany of evidenceanevidence investigation ofof anan investigationinvestigation into the substrate intointo thethe scope. substratesubstrate scope.scope.

H H NH NH N N N Thermolysis N 150 °C S S O Thermolysis S 150 °C S S O S S S S S S S S S SS NN 25a25a 25b25b HH 25c,25c, PostulatedPostulated IntermediateIntermediate NN

NN 25d25d,, 80%80% yield yield SchemeScheme 26. 26. TheThe formation formation of of dibenzo[ dibenzo[aa,,hh]phenazine]phenazine in in high highhigh yield yieldyield from fromfrom the the Herz Herz radical radical [4,33] [[4,33]4,33]... Reactions 2021, 2 197 RReactionseactions 2021 2021, 2, ,2 FOR, FOR PEER PEER REVIEW REVIEW 24 24

4.3.4.3. Synthesis Synthesis of ofPhenothiazines Phenothiazines Mayer,Mayer, Zhivonitko, Zhivonitko,Zhivonitko, Marakov MarakovMarakov and andand co co-workersco-workers-workers have have reported reported on onthe the formation formation of phe- of phe- nothiazinesnothiazines from fromfrom self self-condensationself-condensation-condensation of of ofbenzodithiazoyl benzodithiazoyl benzodithiazoyl radicals radicals [[50]50 [50]].. Two . Two self-condensationself self-condensa--condensa- tionisomertion isomer isomer products, products, products, each each fromeach from from an intermediatean an intermediate intermediate unsubstituted unsubstituted unsubstituted and and fluoro-substituted and fluoro fluoro-substituted-substituted 1,2,3- 1,2,3benzodithiazoyl1,2,3-benzod-benzodithiazoylithiazoyl radical radical radical (26d (26d), (26d were), ),were synthesisedwere synthesised synthesised [92 ].[92] These[92]. These. These crystalline crystalline crystalline compounds compounds compounds were wereisolatedwere isolated isolated in very in in very lowvery low yield low yield yield from from afrom reaction a reactiona reaction mixture mixture mixture (for (for which (for which which the the 1,2,3-benzodithiazoyl the 1,2,3 1,2,3-benzodithi--benzodithi- azoylradicalazoyl radical radical26b was26b 26b detectedwas was detected detected as a minoras as a minora minor intermediate), intermediate), intermediate), but alsobut but also in also higher in higherin (30%)higher (30%) yield (30%) yield by yield slowly by by slowlyreactingslowly reacting reacting the fluorinated the the fluorinated fluorinated 2-triphenylphosphoranimine-substituted 2- triphenylphosphoranimine2-triphenylphosphoranimine-substituted-substituted benzodithiazole benzodithiazole benzodithiazole (26a ) (26aat(26a ambient) at) at ambient ambient temperature temperature temperature in in chloroform in chloroform chloroform (Scheme (Scheme (Scheme 27 27). ).27 It ). is isIt interestingis interesting interesting to to speculateto speculate speculate on on ona aa difference in the isolated product compared to Mayer’s process above [33]. It is likely the differencedifference in in the the isolated isolated product product compared compared to toMayer’s Mayer’s process process above above [33] [33]. It .is It likely is likely the the fluoro substituents, which would substantially reduce the electron density of the ring and fluorofluoro substituents, substituents, which which would would substantially substantially reduce reduce the the electron electron density density of theof the ring ring and and render the substrate very reactive to SNAr processes. renderrender the the substrate substrate very very reactive reactive to toSN SArNAr processes. processes.

F F F F FF F F F F F F F FF N CHCl F N N F F N N CHCl3 3 N N N S SNN S S S S r.t. 7 S F S PPh r.t. days7 days F S S F S F S S F S PPh3 3 F F S F S F Ph P=N F 26a F F 3Ph3P=N F 26a 26b Detected F 26b, , Detected 26c, Postulated intermediate intermediate solution) 26c, Postulated intermediate intermediate(in (in solution) F F F F F N F N S S S S F S N F S N F F F26d, 30% F 26d, 30%

Scheme 27. The synthesis of phenothiazines by self-condensation of benzodithiazoyl radicals [50]. Scheme 27. The synthesis of phenothiazines by self-condensationself-condensation ofof benzodithiazoylbenzodithiazoyl radicalsradicals [[50]50].. The crystal structures of compound 26d [93] and a related regioisomer [94] (that were The crystal structures ofof compoundcompound 26d26d [[93]93] and a related regioisomer [[94]94] (that(that werewere both isolated from a process other than depicted in Scheme 27) were deposited to the both isolatedisolated from from a processa process other other than than depicted depicted in Scheme in Scheme 27) were 27) depositedwere deposited to the CCDC, to the CCDC, and their respective unit cells are shown (Figure 10). Their perfectly planar con- andCCDC their, and respective their respective unit cells unit are showncells are (Figure shown 10 (Figure). Their 10 perfectly). Their perfectly planar conﬁguration planar con- figurationallows for allows uniform forπ uniform-stacking π in-stacking the crystal in the structure, crystal andstructure their, unit and cells their are unit cuboidal cells are (α = figuration allows for uniform π-stacking in the crystal structure, and their unit cells are cuboidalβ = γ = 90(α ◦=). β Aesthetically = γ = 90°). Aesthetically pleasing crystal pleasing structures crystal structures aside, these aside, tetracycles these tetracycles are a novel cuboidal (α = β = γ = 90°). Aesthetically pleasing crystal structures aside, these tetracycles arestructural a novel structural moiety, for moie whichty, for no applicationwhich no application has yet been hasidealised yet been idealised [50]. [50]. are a novel structural moiety, for which no application has yet been idealised [50].

(a) (b) (a) (b) FigureFigure 10. 10. TheThe unit unit cells cells of: ( of:a) 4,6,7,8,9,11 (a) 4,6,7,8,9,11-hexaﬂuoro(1,2,3)dithiazolo(5,4--hexafluoro(1,2,3)dithiazolo(5,4-b)phenothiazineb)phenothiazine (26d) [93] (26d and)[93 (b]) andRelated (b) com- Related poundcompoundFigure 4,5,7,8,9,10 10. The 4,5,7,8,9,10-hexaﬂuoro(1,2,3)dithiazolo(4,5- unit-hexafluoro(1,2,3) cells of: (a) 4,6,7,8,9,11dithiazolo(4,5-hexafluoro(1,2,3)dithiazolo(5,4-c)phenothiazine,c)phenothiazine, with with some-b some)phenothiazine molecules molecules outside outside(26d of) [93] the of and theunit unit( bcell) Related cell showing showing com- the stacking as the unit cell contained only a single molecule [94]. thepound stacking 4,5,7,8,9,10 as the- unithexafluoro(1,2,3) cell containeddithiazolo(4,5 only a single-c molecule)phenothiazine, [94]. with some molecules outside of the unit cell showing the stacking as the unit cell contained only a single molecule [94]. Reactions 2021, 2, FOR PEER REVIEW 25

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We have already discussed how multiple studies have struggled to isolate any crystalline polymorphsWe have already of simpler discussed benzo[1,2,3]dithiazole how multiple studies compounds, have struggled such as tothe isolate parent any Herz crys- salttalline (2) or polymorphshydrolysed sulfone of simpler product benzo[1,2,3]dithiazole (3) obtained from compounds, aniline (1). Indeed, such as thethis parenthas been Herz attemptedsalt (2) orin our hydrolysed own laboratory, sulfone although product (no3) obtainedsuitable crystalline from aniline material (1). Indeed,could be this gen- has eratedbeen without attempted exchanging in our own to a laboratory,large counter although-anion [68] no suitable, as per previous crystalline literature material sug- could gestionsbe generated [4]. An interesting without exchanging consideration to a largeis from counter-anion the degree of [ 68π-],stacking as per previousand its compar- literature isonsuggestions to that displayed [4]. An in interestingFigure 10, with consideration the caveat isthat from such the stacked degree-planar of π-stacking structures and are its possiblecomparison in only to a thatrelatively displayed few circumstances. in Figure 10, with The the benzodithiazolium caveat that such stacked-planaranion of the Herz struc- salttures is a flat, are possible10-π aromatic in only system a relatively but must few be circumstances. supported by a The counterion benzodithiazolium, and hence, any anion crystalof the structure Herz salt is dictated is a flat, by 10- theπ aromatic ionic interactions system but as mustwell as be π supported-stacking. Marakov by a counterion, et al. observedand hence, significant any crystal π-π structureinteractions is dictated in their bycovalent the ionic iminophosphorane interactions as well crystals as π-stacking. (e.g., 26aMarakov, Scheme et27 al.), although observed as significant the triphenylphosphineπ-π interactions substituent in their covalent is large, iminophosphorane a back-to-back arrangementcrystals (e.g., was26a adopted,, Scheme rather 27), althoughthan a lattice as the of triphenylphosphineflat sheets. Stacked sheets substituent are, however is large,, a observedback-to-back with the arrangement aforementioned was adopted, 8-π (non rather-aromatic) than malononitrile a lattice of flat-coupled sheets. Stackedbenzodithi- sheets azolesare, (e.g. however,, Table observed 3) [17,47] with as well the aforementionedas some other compounds 8-π (non-aromatic) to be covered malononitrile-coupled in Section 5.3. In summary,benzodithiazoles using homolytic (e.g., Table processes,3 )[17,47] Herz as well compounds as some other have compounds been reacted to to be form covered un- in usualSection and 5.3privileged. In summary, polycyclic using structures. homolytic processes,Currently Herz, only compounds a handful of have processes been reacted have to beenform demonstrated, unusual and leaving privileged the polycyclicarea ripe for structures. exploitation. Currently, only a handful of processes have been demonstrated, leaving the area ripe for exploitation. 5. Applications from the Electronic Properties of Benzo[1,2,3]dithiazoles 5. Applications from the Electronic Properties of Benzo[1,2,3]dithiazoles While having been first noted in early research that the Herz compounds were in- crediblyWhile intense having dyes, been further first investigation noted in early into research their that electronic the Herz properties compounds has were only incred- re- centlyibly been intense undertaken. dyes, further It was investigation the realisation into theirthat benzodithiazole electronic properties structures has only can recentlyform stablebeen radicals undertaken. that are It nevertheless was the realisation easy to that oxidise benzodithiazole back to the ionic structures ‘Herz cansalt’ form that stablehas increasedradicals scientific that are neverthelessinterest in this easy area. to oxidise back to the ionic ‘Herz salt’ that has increased scientificThe promising interest inelectronic this area. properties of these entities were demonstrated by synthe- sising coordinationThe promising complexes, electronic such properties as the oflithium these bound entities system were demonstrated (Figure 11) [95] by. synthe-The dithiazolesising coordination rings have large complexes, spin densities such as about the lithium the N boundand S systematoms, hence (Figure engaging 11)[95]. i Then intermoleculardithiazole rings interactions have large [95] spin. This densities makes such about compounds the N and intriguing S atoms, aromatic hence engaging ligands in forintermolecular the preparation interactions of new metal [95 ].complexes, This makes especially such compounds if an existing intriguing metal aromaticchelator, ligandssuch for the preparation of new metal complexes, especially if an existing metal chelator, such as o-quinone derivatives, is used as the starting material. as o-quinone derivatives, is used as the starting material.

Figure 11. The structure of a metal–benzodithiazole complex [95]. Figure 11. The structure of a metal–benzodithiazole complex [95]. 5.1. Legacy, Visible-Light Dyes 5.1. Legacy, Visible-Light Dyes A prominent property arising from the highly conjugated π-systems and intense electromagneticA prominent property absorptions arising within from thethe visiblehighly lightconjugated range π is-systems the generation and intense of intensely elec- tromagneticcoloured compounds.absorptions within The benzodithiazole the visible light compoundsrange is the generation were one ofof manyintensely classes col- of ouredintensely compounds. coloured The compounds benzodithiazole discovered compounds by Richard were Herz one when of many investigating classes of intensely the reaction colouredof small compounds aromatic compounds discovered with by polysulﬁdeRichard Herz moieties when [investigating19]. While the the benzodithiazoles reaction of were core in the research of Herz that led to scores of new dye compounds, [19,96,97] Reactions 2021, 2, FOR PEER REVIEW 26

small aromatic compounds with polysulfide moieties [19]. While the benzodithiazoles were core in the research of Herz that led to scores of new dye compounds, [19,96,97] they were mainly utilised as feedstocks for other molecules in which the final structures had lost their benzodithiazole moiety. Indeed, although benzodithiazoles are described as dye Reactions 2021, 2, FOR PEER REVIEWsubstances in several patents [18], there appears no evidence they have ever been com-26

mercialised. Nevertheless, the importance of the Herz reaction in supporting these dis- Reactions 2021, 2 coveries is evident from the fact that many patented dyes [96,97] in the 1920s and 30s199 containsmall aromatic para-chlorides compounds in the withstructure, polysulfide doubtlessly moieties introduce [19]. Whiled during the the benzodithiazoles Herz reaction (wereFigure core 12 ).in the research of Herz that led to scores of new dye compounds, [19,96,97] they theywere weremainly mainly utilised utilised as feedstocks as feedstocks for other for other molecules molecules in which in which the final the final structures structures had OH hadlost their losttheir benzodithiazoleO benzodithiazole moiety. moiety. Indeed, Indeed, although although benzodithiazoles benzodithiazolesH areH described are described as dye N N assubstances dye substances in several inS several patents patents [18]Cl , there [18], appears there appears no evidence no evidence they hav theye ever have been ever beencom- commercialised.mercialised. Nevertheless, Nevertheless, the importance the importance of the of Herz the Herz reaction reaction in supporting in supporting these these dis- discoveriescoveriesCl is evident isS evident from from the the fact fact that that many many patentedCl patented dyes dyesS [96,97] [96,97 ]in inS the the 1920s Cl andand 30s30s contain para-chlorides-chloridesO in thethe structure,structure, doubtlesslydoubtlessly introducedintroduced duringduringOH thethe HerzHerz reactionreaction 'reddish brown vat dye' (1916) (Figure(Dimethyl-6.6'-dichloro-thioindigoFigure 1212).). (1931) Figure 12. Two patented dye molecules that were derived from Herz reaction products, indicating OH the prevalent chlorideO substitution [96,97]. H H S Cl N N 5.2. Near-Infrared Dyes Cl In contrastS to earlier works relying on benzodithiazolesCl S as merelyS synthetic interme-Cl diates, recent studiesO suggest that compounds bearing benzodithiazoleOH moieties indeed 'reddish brown vat dye' (1916) haveDimethyl-6.6'-dichloro-thioindigo applicability due to their (1931)novel absorption and redox properties. Starting with the readilyFigure 12.12. radicalised, Two patentedpatented anti dyedye-aromatic moleculesmolecules structures thatthat werewere derived(e.g.derived, 27a fromfrom, Scheme HerzHerz reactionreaction 28) first products,products, synthesised indicatingindicating by Reedthethe prevalentprevalent et al. [98] chloridechloride using substitutionsubstitution triphenylantimony [[96,97]96,97].. to transform the Herz reaction products, in extension, Makarov et al. have synthesised a range of near-infrared dyes. Two such examples,5.2. Near-InfraredNear 27b- andInfrared 27c , Dyes are shown (Scheme 28) [11]. Compounds with lower bandgap absorptions InInin contrastthe near - toIR earlier range works(typically relying < 1.6 on eV) benzodithiazoles are particularly assought merely after synthetic in the develop- interme- mentdiates, of recentrecent photodetectors, studiesstudies suggestsuggest photovoltaic thatthat compoundscompounds cells and ambipolar bearingbearing benzodithiazolebenzodithiazole field-effect transistors moietiesmoieties [99,100] indeedindeed. Otherhave applicabilitypoly-heteroaromatics, due toto theirtheir including novelnovel absorptionabsorption benzo[1,3,2]dithiazoles, andand redoxredox properties.propert are commonies. StartingStarting in such withwith ap- thethe readily radicalised, anti-aromatic structures (e.g., 27a, Scheme 28) first synthesised by Reed plicationsreadily radicalised, [99], although anti -whataromatic is particular structures about (e.g. these, 27a benzo[1,2,3]dithiazole, Scheme 28) first synthesised derivatives by et al. [98] using triphenylantimony to transform the Herz reaction products, in extension, isReed the etcontrollable al. [98] using redox triphenylantimony activity alongside to transformthe near-IR the wavelength Herz reaction absorption products,, giving in ex- Makarov et al. have synthesised a range of near-infrared dyes. Two such examples, 27b themtension the, Makarovpossibility et of al. an have end synthesised-use in tuneable a range ‘smart of nearmaterials’-infrared [100] dyes.. Two such exam- and 27c, are shown (Scheme 28)[11]. Compounds with lower bandgap absorptions in ples,Mayer 27b and [33] 27c had, are shownshown previously(Scheme 28 )that [11] .phenazine Compounds derivatives with lower could bandgap be accessed absorp- the near-IR range (typically < 1.6 eV) are particularly sought after in the development of throughtions in thethe nearoxidised-IR range radical (typically intermediates < 1.6 eV) (Section are particularly 4.3). Correspondingly, sought after these in the new develop- com- photodetectors, photovoltaic cells and ambipolar field-effect transistors [99,100]. Other poundsment of 27bphotodetectors,–c were thermally photovoltaic stable tocells over and 200 ambipolar °C, and fieldthe yield-effect for transistors the phenazine [99,100] is. poly-heteroaromatics, including benzo[1,3,2]dithiazoles, are common in such applica- similarlyOther poly quite-heteroaromatics, high considering including the complexity benzo[1,3,2]dithiazoles, of the active compound. are common The in redox such be-ap- tions [99], although what is particular about these benzo[1,2,3]dithiazole derivatives is the haviourplications of [99]the ,compounds although what was is studied, particular finding about that these up benzo[1,2,3]dithiazole to five different electronic derivatives states controllable redox activity alongside the near-IR wavelength absorption, giving them the couldis the becontrollable accessed. Eachredox state activity having alongside distinct absorptionthe near-IR in wavelength the near-IR absorptionto UV range,, giving con- possibility of an end-use in tuneable ‘smart materials’ [100]. sistentthem the with possibility the desire of to an produce end-use compounds in tuneable with‘smart tuneable materials’ absorption [100]. properties. Mayer [33] had shown previously that phenazine derivatives could be accessed S S S through the oxidised radical intermediates (Section 4.3).S Correspondingly,N N S these new com- N N N S S pounds 27b2 SbPh–c were thermally stable to over 200 °C, and the yield for the phenazine is S 3 + N N S similarly quite high considering the complexity of the active compound. The redox be- S MeCN, haviour of the compoundsN was studied,N finding that up to five different electronic states 1 h t S N Reflux, Bu tBu could2Cl be accessed. Each stateS S having distinct absorption in the near-IR to UV range, con- 27b, 42% yield 27c, 9% yield 27a, 'Herz salt'sistent with the desire to produce compounds with tuneable absorption properties.

Scheme 28. The synthetic procedure of Makarov et al. to form the active S benzodithiazole benzodithiazole-containingS -containingS compounds [[1111]].. S N N S N N N S S Mayer2 [SbPh33] had shown previously that phenazine derivatives could be accessed S 5.3. Semiconductors3 + N N S through the oxidised radical intermediates (Section 4.3). Correspondingly, these new S An organicMeCN, solid can be a semiconductor if the energy◦ of its band gap (Eg) between compounds 27b–c wereN thermallyN stable to over 200 C, and the yield for the phenazine 1 h t S N its occupiedReflux, and vacant electronic states is sufficientlyBu small that the vacanttBu states can be is2Cl similarly quite high consideringS S the complexity of the active compound. The redox 27b, 42% yield 27c, 9% yield 27a, 'Herz salt'behaviour of the compounds was studied, ﬁnding that up to ﬁve different electronic states could be accessed. Each state having distinct absorption in the near-IR to UV range, Scheme 28. The syntheticconsistent procedure of with Makarov the desire et al. to form produce the active compounds benzodithiazole with tuneable-containing absorption compounds properties. [11].

5.3. Semiconductors

An organic solidsolid cancan bebe aa semiconductorsemiconductor ifif thethe energyenergy ofof itsits bandband gapgap (E(Egg)) betweenbetween itsits occupied and and vacant vacant electronic electronic states states is is sufficiently sufﬁciently small small that that the the vacant vacant states states can can be be occupied thermally. If Eg is too large, then the vacant orbitals cannot be populated without an alternative energy input (such as radiation) and the material acts as an insulator. Reactions 2021, 2, FOR PEER REVIEW 3 R eactions 2021, 2, FOR PEER REVIEW 3

Reactions 2021, 2 200

Materials with no band gap at all are known as metallic conductors. The discovery of the Herz radicals in the late 1970s did not immediately lead to research into the charge-transfer properties in the solid-state for application as organic conductors. Several studies in the 1980s focussed instead on the alternative benzo[1,3,2]dithiazoles [101–103]. Given the extensive research within the ﬁeld in the 1980s and 90s [104], it is somewhat surprising that the charge-transfer chemistry of benzo[1,2,3]dithiazoles was seemingly not considered until a computational investigation by Genin and Hoffmann [105] (1997) and later an experimental one by Barclay et al. [98] (1998). We have discussed how these anti-aromatic structures in the neutral form are easily oxidised to form stable radical cations (Section 2.6), and in particular cases, this can generate conductivity, depending on the solid-state − arrangement. Different solids, perchlorate and FSO3 salts (28a–d), were prepared by Barclay et al. (in either a 1:1 or 3:2—organic compound: inorganic ion ratio), and their conductivities were measured in the order of 10−2 S cm−1 for the 3:2 complexes (sufﬁcient to class them as solid semiconductors, 28b, 28d, Table4). Separately, a third solid ( 28e) was formed with naphtho[2,1-d:6,5-dA]bis([1,2,3]dithiazole) and BF counter ion (3:2 ratio) and 4 thePercentages conductivity refer to was pure of isolated the same compounds (10−2 S cm. −1) order of magnitude (Table4)[53]. Percentages refer to pure isolated compounds.

TableTable 4. 4.Five Five different different solids solids based based on on the the benzo[1,2,3]dithiazole benzo[1,2,3]dithiazole moiety moiety and and their their measured measured conduc- con- Tableductivities 4. Five at roomdifferent temperature solids based [53,98] on . the benzo[1,2,3]dithiazole moiety and their measured con- tivitiesductivities at room at room temperature temperature [53,98 [53,98]]. . −1 Solid Formula Measured Conductivity/S cm−1 (One Significant Figure) SolidSolid Formula MeasuredMeasured Conductivity Conductivity/S/S cm cm−−11 ((OneOne SigniﬁcantSignificant Figure) Figure)

−5 10−−55 1010−5

28a 28a

−−22 1010−2 10−2

28b 28b

−5 10−5 Reactions 2021, 2, FOR PEER REVIEW 10−5 4 R eactions 2021, 2, FOR PEER REVIEW 10−5 4 10

28c 28c

−−22 1010−2

28d

−2 10−2 10−2

28e 28e

Table 5. The synthesis of conducting solid benzobis[1,2,3]dithiazoyl radicals across several publications by Oakley et al. [55,111–115].

a a Synthesised using a quinone intermediate and then reduced with an electrochemical method [111]. b Reduced from the SbF6 salt (rather than TfO) with a Fe–Cp complex rather than electro- [111]. b Reduced from the SbF6 salt (rather than TfO) with a Fe–Cp complex rather than electrochemically [55]. Percentages refer to pure isolated yields for the final reduction (radical formation) step. Reactions 2021, 2, FOR PEER REVIEW 28

S S N S S [FSO3]2 10−2 N 3

28d

N S S S [BF4]2 S 10−2 N 3 Reactions 2021, 2 201 28e

SubsequentSubsequent findings findings relating relating to the electronic electronic properties of this series were reviewed byby Lonchakov et et al. al. [48] [48] supported by a computational study [106] [106];; the properties and behaviourbehaviour of of such such benzo[1,2,3]dithiazole benzo[1,2,3]dithiazole structures structures are compared to other N N-heterocyclic-heterocyclic electronelectron acceptors. Oakley etet al.al. firstfirst reportedreported an an experimental experimental investigation investigation into into the the electro- elec- trochemicalchemical potential potential of benzo[1,2,3]dithiazoles of benzo[1,2,3]dithiazoles and laterand isolatedlater isolated a Zwitterionic a Zwitterionic benzobis benzo-[1,2,3] bisdithiazole[1,2,3]dithiazole compound compound (29d, Scheme (29d, 29Scheme), a privileged 29), a privileged 17π system 17π [ 54system]. The [54] new. The Zwitteri- new Zwitterioniconic benzodithiazole benzodithiazole (29d), crystallised (29d), crystallised in the absence in the absence of other of counter other ionscounter or solvates, ions or solvates,arranged arranged into flat into sheets flat of sheets a ‘brick of a wall’ ‘brick motif, wall’ whichmotif, possessedwhich possessed conductivity conductivity of about of about10−3 S 10 cm−3 −S1 cmat−1 room at room temperature temperature and pressureand pressure (Figure (Figure 13). Remarkably,13). Remarkably, under under a pres- a pressuresure of 8 of GPa, 8 GPa, the the material’s material’s band band gap gap decreased decreased further, further, and and essentially,essentially, itit becamebecame a metallicmetallic conductor, conductor, with with a aconductivity conductivity of of >10 >10 S cm S cm−1. −The1. Thepreparation preparation of the of parent the parent ben- zobenzobis[1,2,3]dithiazolebis[1,2,3]dithiazole (29b) ( 29bis synthetically) is synthetically noteworthy noteworthy as it required as it required the unusual the unusual installa- in- tionstallation of two of benzo[1,2,3]dithiazole two benzo[1,2,3]dithiazole rings ringsvia a diaminobenzene via a diaminobenzene (29a) (starting29a) starting material material with disulfurwith disulfur dichloride dichloride (Scheme (Scheme 19). The 19 ).conversion The conversion to the ‘Herz to the radical’ ‘Herz radical’form (29c form) electro- (29c) chemicallyelectrochemically [44] or [to44 the] or zwitterionic to the zwitterionic form (29d form) by (29d reacting) by reacting with a withproton a proton sponge sponge is read- is ilyreadily mediated mediated (Scheme (Scheme 29) [54] 29)[. 54].

OH O

H2N NH2 1. S2Cl2 (9 equiv.), N N MeCN, S S S S .2HCl TfO 2. X AgOTf X Proton sponge, X = OH 29a 29b O O O Electrochemical N N e.g X = Cl, Me, Ph N N N N S S S S S S S S S S S S X O O 29c Herz radical Reactions 2021, 2, FOR PEER REVIEW , 29d, Zwitterion form 29

SchemeScheme 29. TheThe synthesis synthesis of of the the parent parent Herz salt and continuation to either radical or Zwitterionic forms [[44,54]44,54]..

(a) (b)

Figure 13. The crystal structures and unit cells of the Zwitterionic product ( (SchemeScheme 29) synthesised by Oakley et al. in the Schemesolid state. 3. 0 (Åa) and showing the space the perfectly-stackedgroup is Cmc21 [107] ﬂat. sheets of molecules and (b) looking ‘through’ the sheets. The distance

between the sheets (or the length of the shortest edge in the unit cell) is 3.0 Å and the space group is Cmc21 [107]. Subsequently, the same group synthesised the equivalent to molecule 29d, but with the 2-positions of the dithiazole rings substituted with selenium, rather than sulphur (29e, Figure 14) [108]. The intention was to form a crystalline polymorph with perfectly stacked sheets, analogous to their above example (Figure 13), though ultimately, no such polymorph could be formed. Instead, solids of three alternative phases were synthesised in space groups P21/c and R3c (Figure 14, the thiazole rings are slightly out-of-plane with the benzene ring) with conductivities measured. At room temperature and pressure, the P21/c polymorph was a Mott insulator with a low conductivity at 10−5 S cm−1. The R3c phase fared better at 10−2 S cm−1 and, similarly to the Cmc21 sulphur analogue (Figure 13), became a metallic conductor at 6 GPa.

O N N Se Se S S O 29e

(a) (b) Figure 14. Two crystal structures and unit cells of the selenium Zwitterionic product (29e) synthesised by Oakley et al. in the solid-state [108]: (a) the P21/c (mott insulator) phase [109] and (b) the R3c (semiconductive) phase [110].

A parallel investigation that included solids based on the benzobis[1,2,3]dithiazole neutral radicals (Scheme 29) was performed [111–115]. The desired ‘brick wall’ sheet structure (space group Cmc21, as in Figure 13) was formed with the fluoro substituent (30b, Table 5), which possessed marginally improved room-temperature conductivity (at Reactions 2021, 2, FOR PEER REVIEW 29

(a) (b) Reactions 2021, 2 202 Figure 13. The crystal structures and unit cells of the Zwitterionic product (Scheme 29) synthesised by Oakley et al. in the Scheme 3. 0 Å and the space group is Cmc21 [107].

Subsequently,Subsequently, the same group synthesised the equivalent to molecule 29d,, but with thethe 2 2-positions-positions of of the the dithiazole dithiazole rings rings substituted substituted with with selenium, selenium, rather rather than thansulphur sulphur (29e, Figure(29e, Figure 14) [108] 14)[. The108 ].intention The intention was to wasform to a formcrystalline a crystalline polymorph polymorph with perfectly with perfectly stacked sheets,stacked analogous sheets, analogous to their toabove their example above example (Figure (Figure13), though 13), though ultimately, ultimately, no such no poly- such morphpolymorph could could be formed. be formed. Instead, Instead, solids solids of three of three alternative alternative phases phases were were synthesised synthesised in space groups P21/c and R3c (Figure 14, the thiazole rings are slightly out-of-plane with the in space groups P21/c and R3c (Figure 14, the thiazole rings are slightly out-of-plane with benzenethe benzene ring) ring) with with conductivities conductivities measured. measured. At room At room temperature temperature and pressure, and pressure, the P2 the1/c polymorph was a Mott insulator with a low conductivity at 10−5 S cm−5−1. The− R3c1 phase P21/c polymorph was a Mott insulator with a low conductivity at 10 S cm . The R3c −2 −−12 −1 1 faredphase better fared at better 10 atS cm 10 andS cm, similarlyand, similarly to the Cmc2 to the sulphur Cmc21 analoguesulphur analogue (Figure 13(Figure), became 13), abecame metallic a metallicconductor conductor at 6 GPa. at 6 GPa.

O N N Se Se S S O 29e

(a) (b)

Figure 14. Two crystal structures and unit cells of the selenium Zwitterionic product (29e) synthesised by Oakley et al. in the solid-state [108]: (a) the P21/c (mott insulator) phase [109] and (b) the R3c (semiconductive) phase [110]. the solid-state [108]: (a) the P21/c (mott insulator) phase [109] and (b) the R3c (semiconductive) phase [110].

AA parallel investigationinvestigation that that included included solids solids based based on the on benzo the bisbenzo[1,2,3]dithiazolebis[1,2,3]dithiazole neutral neutralradicals radicals (Scheme 29(Scheme) was performed 29) was performed [111–115]. The [111 desired–115]. ‘brickThe desired wall’ sheet ‘brick structure wall’ (spacesheet structuregroup Cmc2 (space1, as ingroup Figure Cmc2 13) was1, as formed in Figure with 13 the) fluorowas formed substituent with ( 30bthe, Tablefluoro5 ),substituent which pos- (sessed30b, Table marginally 5), which improved possessed room-temperature marginally improved conductivity room (at-temperature2 × 10−2 S cmconductivity−1) compared (at to the Zwitterionic benzobisdithiazole solids (Scheme 29) [44,54,108]. The structures bearing bulkier substituents (30a (OAc), 30f (OMe) and 30g (SMe)) instead formed P21/c crystals (as in Figure 14a) and thus acted as Mott insulators. Seven different benzobisdithiazoles were synthesised as the Herz salt, and each could be reduced to the neutral radical (30a–g, following an ion-exchange) electrochemically [111]; over time, a library of semi-conducting radical solids was built up across the publications (Table5). Reactions 2021, 2, FOR PEER REVIEW 4

Reactions 2021, 2, FOR PEER REVIEW 4

10−2 10−2

28d 28d

10−2 10−2 Reactions 2021, 2 203

28e 28e

TableTable 5. 5.The 5. TheThe synthesis synthesissynthesis of conducting of of conducting conducting solid solid solidbenzo benzobis benzo[1,2,3]dithiazoylbisbis[1,2,3]dithiazoyl[1,2,3]dithiazoyl radicals radicals radicals across across several across several publica- several tionspublicationspublications by Oakley by by Oakley et Oakley al. [55 et et,111 al.al. – [55,111[55,111115]. –115]..

a Synthesised using a quinone intermediate and then reduced with an electrochemical method [111]. b Reduced from the SbF6 salt (rather than TfO) with a Fe–Cp complex rather than electro- a SynthesisedSynthesised using using a quinonea quinone intermediate intermediate and thenand reducedthen reduced with an with electrochemical an electrochemical method [111 method]. b Reduced chemically [55]. Percentages refer to pure isolated yields for the final reduction (radical formation) from[111] the. b Reduced SbF6 salt (ratherfrom the than SbF TfO)6 salt with (rather a Fe–Cp than complex TfO) rather with thana Fe electrochemically–Cp complex rather [55]. Percentagesthan electro- refer to step. purechemically isolated [55] yields. Percentages for the ﬁnal reductionrefer to pure (radical isolated formation) yields step. for the final reduction (radical formation) step. 5.4. Photovoltaic or Electrochemical Cells: The Next Application? We have seen how organic materials with near-infrared absorption/emission characteristics may have applicability to photovoltaics, as well as elaborated in recent review articles [99,100]. The related benzo[1,3,2]dithiazole moiety appears in recent publications relating to solar cells [1,116]. Besides the suggestion by Makarov et al. that these titled [1,2,3]dithiazole structures could feature in photovoltaic materials due to their absorbance characteristics [11], there does not yet appear any further consideration described in the literature. To conclude this section, we note that Zhang and Tuttle have recently published a report into the use of these same compound series as organic electrode materials for a targeted end-use in batteries [117]. Their benzodithiazole-based solid retained 94% of its initial energy capacity after 400 charges/discharge cycles [117], further demonstrating the potential applicability of these conductive properties.

a report into the use of these same compound series as organic electrode materials for a targeted end-use in batteries [117]. Their benzodithiazole-based solid retained 94% of its initial energy capacity after 400 charges/discharge cycles [117], further demonstrating the potential applicability of these conductive properties.

6. Conclusions Today more than ever, the study of compounds containing benzo[1,2,3]dithiazole groups is an active area in the continuously emerging topics of materials chemistry. The Reactions 2021, 2 204 historic Herz reaction remaining the principal method of synthesis. A range of transformations from these Herz compounds has been developed. The ease by which these synthesised Herz compounds can radicalise has provided easy access to some very interesting structuressynthesised with Herz potentially compounds important can radicalise electronic has properties. provided easy The access authors to some look veryforward interest- to theing continued structures appearance with potentially of this important fascinating electronic ring system properties. in future The literature. authors look forward to the continued appearance of this fascinating ring system in future literature. Author Contributions: All authors contributed to, have read and agreed to the published version ofAuthor the manuscript. Contributions: AlexanderBoth Nicholls authors contributedperformed the to, haveinvestigation read and and agreed writing to the of published the original version draft. of Ianthe Baxendale manuscript. performed A.J.N. performed the supervision the investigation, review and and editing writing. All of authors the original have draft. read I.R.B. and agreed performed to thethe published supervision, version review of the and manuscript. editing. Both authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Funding: This research received no external funding. Data Availability Statement: This article presents no new data of our own. All data presented comesData from Availability the indicated Statement: sourceThiss. article presents no new data of our own. All data presented comes Acknowledgments:from the indicated In sources. memory of the late inventor of the Herz reaction, Richard Herz (1867–1936) [19]Acknowledgments:. Crystal structure Inimages memory shown of thethroughout late inventor are original of the to Herz the reaction,authors and Richard were Herzprocessed (1867– using1936) Olex2 [19]. Crystalsoftware structure [118] using images the showndata from throughout the indicated are original sources. to the authors and were processed using Olex2 software [118] using the data from the indicated sources.

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