& Thiourea Oxides

Recent Developments in the Chemistry of Thiourea Oxides

Sergei V. Makarov,*[a] Attila K. Horv�th,[b] Radu Silaghi-Dumitrescu,[c] and Qingyu Gao[d]

Chem. Eur. J. 2014, 20, 14164 – 14176 � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim14164

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Abstract: Thiourea dioxide is one of the best known, impor-tant, and stable products of thiourea oxidation. This com-pound has long been considered as an effective reducingagent for many years. Traditional areas of its application in-clude the textile and paper industries. In recent years, how-ever, thiourea dioxides and trioxides have been widely usedin new fields including organocatalytic, polymerization, and

phase-transfer reactions; reduction of graphene and graph-ite oxides; bitumen modifications; synthesis of guanidinesand their derivatives; and studying nonlinear dynamical phe-nomena in chemical kinetics. The review gives a detailedsurvey of the latest developments and main trends in thechemistry and application of thiourea mon-, di-, andtrioxides.

Introduction

Wide varieties of reducing agents, such as sodium boro-hydride, dithionite, hydroxymethanesulfinate (rongalite), hypo-phosphite, ascorbic acid, samarium diiodide, lithium aluminiumhydride, titanium(III) citrate, zinc, thiols, glucose, and so forth,have been extensively used in chemistry and chemical technol-ogy.[1] Even within this long list, thiourea dioxide (TDO) occu-pies a special place, especially as its versatile properties extenddistinctly beyond those of a simple reducing agent. While TDOhas long been used in chemistry and chemical technology,[2] inthe last 15–20 years traditional as well as new fields of its ap-plication have been developed, both theoretical and practicalaspects, such as reduction of graphene[3a–f] and graphite oxi-des;[3g] synthesis of metal sulfides[4a] and preparation of nano-meter metal powders;[4b] organic synthesis[5] including organo-catalytic,[6] phase-transfer[7] and polymerization reactions;[8] bi-tumen modifications;[9] and the study of nonlinear dynamicalphenomena in chemical kinetics.[10a–c] Derivatives of TDO, suchas N,N’-dimethylthiourea dioxide have also been successfullyapplied in the latter field.[10d] Notably, the applications men-tioned above do not only exploit the well-known reducingproperty of TDO, but rather its rich chemistry involving unusu-al structure, ability to rearrange in aqueous solutions, verycomplex decomposition in different solvents, and so forth.Being a potent reducing agent in alkaline aqueous solutions,thiourea dioxide serves as an effective green oxidant in combi-nation with peroxides.[6f] In contrast to the redox reactions inwhich the sulfur-containing part of TDO plays the governingrole, it is the nitrogen-part of thiourea dioxide and trioxidethat determines their reactivity in the synthesis of guanidinesand its derivatives.[11]

Thiourea dioxide can also serve as a precursor in the synthe-sis of unusual inorganic sulfur-containing compounds, such assulfoxylic acid and its anions in aqueous solutions,[12] whileother thiourea oxides also have perspectives as precursors ofother, almost completely unknown simple sulfur compounds,such as HSOH.[13] Thiourea oxides, including TDO, are also in-termediates in the oxidation of thioureas, including some bio-medically relevant processes—as, in general, more often thannot the physiological effects of the sulfur-containing com-pounds entail S-oxygenation.[14] Beyond these undoubtedly in-teresting applications and implications of TDO, it should benoted that the properties and potential effectiveness of thiscompound, and especially of its derivatives, are still unknownto many chemists. Very often, even for the same compound inthe same state, authors use different formulae ((NH2)2CSO orNH2NHCSOH; (NH2)2CSO2 or NH2NHCSO2H; ((NH2)2CSO3 orNH2NHCSO3H) and different names—thiourea monoxide, ami-noiminomethanesulfenic acid, and formamidinesulfenic acid;thiourea dioxide, aminoiminomethanesulfinic acid, and forma-midinesulfinic acid; and thiourea trioxide, aminoiminometha-nesulfonic acid, and formamidinesulfonic acid, respectively. Inparticular, information on thiourea mono- and trioxides is veryscarce. There is only one relatively old review devoted to themore notable sulfur-containing reducing agents with C�S andS�S bonds: dithionite, rongalite, and thiourea dioxide.[2] Sincethen, at least two reviews on related thiourea dioxide com-pounds—sodium dithionite[15] and sodium hydroxymethanesul-finate[16]—have been published, and a review on sulfoxylic acid(the key product of the decomposition of thiourea dioxide)and its anions and ethers is in press.[17] There is, however, nodedicated review on thiourea dioxide and other thioureaoxides. Here, we review the most important trends in thechemistry of thiourea oxides that have mostly appeared afterpublication of the review mentioned above,[2] with a generalfocus on the past 13 years. Earlier papers will be discussedonly to the extent that they were not covered in detail inreference [2].

Synthesis and structure

The first synthesis of thiourea dioxide (TDO) from thiourea andhydrogen peroxide in aqueous solution was reported by Bar-nett in 1910.[18] For many years TDO remained the only knownoxide of thioureas, until Bçeseken[19] and later Walter and co-workers[20] published a series of papers on the synthesis of thedioxides and trioxides of thioureas in aqueous solutions. The

[a] Prof. S. V. MakarovState University of Chemistry and TechnologySheremetevsky str. 7, 153000, Ivanovo (Russia)Fax: (+ 7) 4932416693E-mail : makarov@isuct.ru

[b] Prof. A. K. Horv�thDepartment of Inorganic ChemistryUniversity of P�cs, Ifjffls�g u. 6, 7624, P�cs (Hungary)

[c] Prof. R. Silaghi-DumitrescuUniversitate Babes-BolyaiArany Janos str. 11, RO-400024, Cluj-Napoca (Romania)

[d] Prof. Q. GaoSchool of Chemical EngineeringChina University of Mining and TechnologyXuzhou, 221116 (P. R. China)

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synthesis of dioxides and trioxides was also carried out by Yar-ovenko and Lastovskii ;[21] Miller, Bischoff and Pae;[22] De Filippoand co-workers;[23] Havel and Kluttz;[24] Kim and co-workers;[25]

and Maryanoff and co-workers.[26] It should be noted that themost convenient oxidant to prepare thiourea trioxide (TTO) isperacetic acid.[25] An electrochemical procedure for the synthe-sis of thiourea trioxides has also been proposed.[27] A compre-hensive list of synthesized thiourea dioxides and trioxides withthe corresponding references can be found in reference [2].The oxidation of TDO to TTO can be easily verified using UV/Vis spectroscopy: TDO has a broad absorption band witha maximum at 269 nm, while TTO only displays a maximum at205 nm.[11a] The IR spectra of TTO and of its phenyl derivativealso exhibit many differences from that of TDO,[11a] especially inthe range between 1000 and 1500 cm�1.[11a, 26b] Thus, TTO andN-phenylthiourea trioxides show characteristic bands at 1056,1250 and 1067, 1232 cm�1, respectively, as opposed to 1064,1431 and 1010, 1096 cm�1 for the corresponding dioxides,respectively. Detailed data on 1H, 13C, and 17O NMR spectra ofthiourea oxides can also be found in several reports.[11a, 26b, 28–31]

The reaction products of thiourea and H2O2 (or other perox-ides) depend strongly (in terms of identity and distribution) onpH. The major products in strongly acidic media (as well as inthe presence of metal ions) are formamidine disulfide(NH2)(NH)CSSC(NH)(NH2) salts.[32] The kinetics and mechanismof the reactions of thiourea and N,N’-dialkylthioureas with hy-drogen peroxides in acidic media was studied by Hoffmannand Edwards.[32a] In their opinion, thioureas act as nucleophilesby replacing the peroxide oxygen. Later, however, Saha andGreenslade[33] have shown that upon oxidation of thiourea byhydrogen peroxide the carbamidinothiyl radical NH2(=NH)CSC isformed, the most intense EPR signal being observed atpH 2.5–3.0.

In slightly acidic and neutral aqueous solutions there isa consecutive formation of mono-, di-, and trioxides in thecourse of oxidation of thioureas by peroxides. In most casesthe most unstable compounds are monoxides. Relativelystable monoxides are formed from thiourea derivatives withbulky substitutes, such as N-phenyl- and ethylenethiourea.[14]

Recently, Simoyi and co-workers have shown[13] that oxidationof tetramethylthiourea by bromate entailed the formation oftetramethylthiourea sulfenic acid (monoxide), as evidenced bythe electrospray ionization mass spectrum of the dynamicreaction solution (Figure 1).

This S-oxide was then oxidized, yielding tetramethylurea andsulfate as the final products of the reaction. There was no evi-dence for the formation of the sulfinic and sulfonic acids in theoxidation pathway. The attempts to synthesize dioxide and tri-oxides failed (presumably via reaction of tetramethylthiourea

with hydrogen peroxide). Interestingly, the authors proposedthat cleavage of the C�S bond occurs at this point, yieldingthe highly reduced sulfur leaving group HSOH, which is subse-

Figure 1. Oxidation of tetramethylthiourea by bromate to tetramethylthio-urea sulfenic acid.

Qingyu Gao, born in 1965, received hisdoctorate from Nankai University(China) in1996. He has been worked as a postdoctoralfellow and visiting scholar at several univer-sities such as Stanford University (USA), Uni-versity of Missouri-Columbia (USA), Universityof Windsor (Canada), Brandeis University(USA), and Boston University (USA). In 1998,he received a faculty position in ChinaUniversity of Mining and Technology (China)and was promoted to full professor in 2002.Research interests: spatiotemporal dynamicsand soft matter, sulfur chemistry related tocomplex reactions and clean energy.

Attila K. Horv�th was born in 1971, Veszpr�m(Hungary). After spending two years as apostdoctoral fellow at Brandeis University,Waltham, MA (USA) and receiving his Ph.D.in 2000 at University of Szeged (Hungary) heworked at Szeged as a teaching assistant until2008. Then he moved to the University of P�cs(Hungary) and currently he is an associateprofessor there. He has also worked as avisiting scholar at China University of Miningand Technology (China).. His current researchinterest mainly focuses on elucidating thekinetics and mechanism of the reactionsbetween sulfur- and halogen-containing inor-ganic species, including those ones that often exhibit nonlinear dynamicphenomena.

Sergei V. Makarov was born in Moscow(Russia) in 1956. He received his Ph.D. fromIvanovo State University of Chemistry andTechnology (ISUCT, Russia) in 1986. In 2003 hewas appointed as a Professor of PhysicalChemistry at ISUCT, where he is currently isthe Head of Department of Food Chemistry. Hehas worked as a visiting scholar at WestVirginia University (USA), University of Erlan-gen-Nuremberg (Germany), and China Univer-sity of Mining and Technology (China). He is amember of the Editorial Board for J. Coord.Chem. Research interests: chemistry of sulfur-containing reducing agents, kinetics andmechanisms of reactions catalyzed by metallophthalocyanines, and redoxtransformations of cobalamins.

Radu Silaghi-Dumitrescu has completed twoPh.D.s (2004 University of Georgia in AthensGA (USA) and 2005 Babes-Bolyai University(BBU, Romania)) and post-doctoral research(2004-2006, University of Essex (UK)) and iscurrently an associate professor and presidentof the Scientific Council at BBU. His researchinterests are centered on small moleculeactivation by metalloproteins, with focus onunusual oxidation states and with ramifica-tions into oxidative and nitrosative stress,blood substitutes, anticancer drug, naturalextracts with antioxidant and biological ef-fects, and biopolymer structure.

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quently rapidly oxidized to sulfate. Evidently, such a pathwaywould no longer allow the formation of di- and trioxides. Partof this reactivity may be dictated by the fact that the reactionsof the tetramethyl derivatives of thiourea monoxide are signifi-cantly more sluggish than those of the corresponding deriva-tives of di- and trioxide. Consequently, di- and trioxide couldnot be detected during the course of the reaction, but it doesnot necessarily mean that HSOH is the precursor of theformation of sulfate ion.

Zhou, Peng, and Tao studied the reaction mechanism of theoxidation of thiourea by hydrogen peroxide in the gas stateusing density functional theory (BH&HLYP and B3LYP) and abinitio methods.[34a] They considered two pathways to the finalproduct of oxidation—aminoiminomethanesulfinic acid(NH2)(NH)CSO2H (AIMSA), which is a tautomer of TDO(Figure 2). Pathway I includes three reactions (R1–R3). The ini-

tial oxidation of thiourea by a H2O2 molecule (R1) forms amino-iminomethanesulfenic acid (intermediate 1), a tautomer of thi-ourea monoxide, TMO, and H2O. Isomerization of amino-iminomethanesulfenic acid (R2) forms a thiourea monoxide(intermediate 2). Further oxidation (R3) of thiourea monoxide(intermediate 2) by a H2O2 molecule produces aminoimino-methanesulfinic acid (final product). Path II includes tworeactions, the initial oxidation (R1), and then furtheroxidation of the aminoiminomethanesulfenic acid (intermedi-ate 1) by a second H2O2 molecule (R4), yielding the finalproduct :

Because the energy of activation DE�, the enthalpy of activa-tion DH� and the Gibbs free energy of activation DG� of reac-tion 4 (R4) predicted by pathway II are higher than those forthe other reactions, pathway I seems to be more feasible. Fur-thermore, the authors subsequently showed that the processis more facile and can go to further completion when assistedby water and hydroxide, in good agreement with experi-ment.[34b]

The enthalpies of combustion of thiourea, formamidine di-sulfide dihydrochloride, thiourea dioxide, and thiourea trioxidewere measured using an oxygen bomb calorimeter, fromwhich the molar standard enthalpies of formation of the lastthree compounds were deduced to be 8.19, �431.49, and�833.32 kJ mol�1, respectively.[35] The molar standard enthal-pies of reaction for the formation of formamidine disulfidedihydrochloride, thiourea dioxide, and thiourea trioxide

from the reaction between thiourea and hydrogen peroxidewere calculated utilizing the data of combustion enthalpiesas well as the formation enthalpies, with essentially identicalresults : 127.11–127.12, �543.66 to �543.64 and �1043.56 to�1043.53 kJ mol�1, respectively.

In liver microsomes, it has been shown that flavin-containingmonooxygenase catalyzes the S-oxygenation of thiourea tothe reactive electrophilic formamidinesulfenic acid and forma-midinesulfinic acid (Scheme 1).[36]

It is a key question whether the formation of formamidinedisulfide and that of thiourea dioxide occur in parallel reac-tions or consecutive pathways during the course of the oxida-tion of thiourea. Chatterjee et al. have studied the oxidation ofthiourea (TU) by H2O2 in presence of the ruthenium complex,[RuIII(edta)(H2O)]� (edta4�= ethylenediaminetetraacetate) atpH 4.9.[37] HPLC product analysis revealed the formation of for-mamidine disulfide (FDS) as a major product at the end of thecatalytic process; formation of other products, including thio-urea dioxide, thiourea trioxide, and sulfate, was also observedafter longer reaction times. The authors’[37] in fact determineda rate constant for the conversion of formamidine disulfide tothiourea dioxide at 25 8C, of 0.0058 m

�1 s�1.Gao and co-workers, based on HPLC data on the oxidation

of thiourea and formamidine disulfide by hydrogen peroxi-de,[32b, 38, 39] propose that even in strongly acidic solutions(pH 1.50) the first intermediate of reaction between TU andH2O2 is thiourea monoxide (k = 0.115 m

�1 s�1), but not FDS, andthat the latter compound is formed from the reaction indicat-ed below [Eq. (1)] with a normal second-order reaction withk = 4.5 m

�1 s�1. Subsequently, the following reaction sequencetakes place [Eqs. (2)–7()] .

HOSCðNHÞNH2 þ SCðNH2Þ2 $ NH2ðNHÞCSSCðNHÞNH2 þ H2O

ð1Þ

NH2ðNHÞCSSCðNHÞNH2 þ H2O2 ! 2HOSCðNHÞNH2 ð2Þ

HOSCðNHÞNH2 þ H2O2 ! HO2SCðNHÞNH2 þ H2O ð3Þ

HO2SCðNHÞNH2 þ H2O2 ! HO3SCðNHÞNH2 þ H2O ð4Þ

HO3SCðNHÞNH2 þ H2O! HSO3� þ OCðNH2Þ2 þ Hþ ð5Þ

Scheme 1. Microsomal oxidation of thiourea.

Figure 2. Proposed mechanism of oxidation of thiourea by hydrogen perox-ide.

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HSO3� þ H2O2 ! SO4

2� þ H2Oþ Hþ ð6Þ

NH2ðNHÞCSSCðNHÞNH2 ! SCðNH2Þ2 þ Sþ products ð7Þ

There is thus, some contradiction on the sequence of forma-tion of intermediates during the oxidation of thioureas by per-oxides. Seemingly, in the presence of complexes or salts ofredox active metals carbamidinothiyl radical NH2(NH)CSC is a pri-mary intermediate, further yielding formamidine disulfidethrough dimerization.[33] It is also conceivable that Equation (1)is reversible, meaning that FDS can be treated as a primarysource of thiourea monoxide and then further, with excess per-oxide, as a source of di- and trioxide. In the absence of com-plexes or salts of redox active metals, thiourea acts as a nucleo-philic agent by replacing one of the oxygen atom of peroxidesin a simple, formal, oxygen-transfer process.[32a] Therefore, de-pending on the experimental conditions, monoxide eitherforms directly from thiourea or from FDS; the composition offinal products will strongly be affected by the molar ratio of re-actants and pH. The influence of acidity on the stability of allproducts of thiourea oxidation will be discussed later (seebelow).[29, 30]

The structure of TDO was first reported by Sullivan and Har-greaves,[40] and later reinvestigated by Chen and Wang[41] aswell as by Song and co-workers.[42] In the solid state TDO existsin the form of (NH2)2CSO2, with a pyramidal CSO2 group; theS�O and C�N bond lengths are 1.496 and 1.296 �, respectively,and the C�S bond (1.867 �) is much longer than in thiourea(1.716 �) (see: Table 1). This C�S bond is one of the longestcarbon–sulfur bonds known in chemistry ;[43] a longer C�Sbond was reported for the TDO derivative N,N’-dimethylthiour-ea dioxide (1.880 �[44]) and the 1,3-di-tert-butylimidazolidin-2-ylidene.SO2 (2.030 �).[45] The C�S bond lengthening is likelydue to the antibonding interaction between the filledp-orbitals in the CN2 central unit and the sulfur lone pair.[44]

Using X-ray data, Chen and Wang[41] have concluded thatthe C�S bond in TDO is essentially a single bond. Song andco-workers[42] suggested that TDO is a combination of twoforms (see Figure 3).

In 2003 Denk and co-workers[45] presented experimental evi-dence (NMR spectroscopy, X-ray crystallographic data) andquantum chemical calculations indicating that thiourea diox-ides are not sulfenes or sulfur ylides, but rather Lewis acid–base adducts of diaminocarbenes with a very weak C�S bondenergy, so that TDO should be described as the structureshown in Figure 4.

From this point of view the syn-thesis of TDO in 1910[18] can betreated as a first synthesis ofa stable carbene complex. Kis andco-workers[46] reported computa-tional data (DFT and Hartree–Fock)of the structure of TDO (zwitterion-ic vs. carbenoid) and the nature ofthe unusually long C�S bond. Thus, natural bond orbital (NBO)partial atomic charges on TDO showed that there is onlya small charge separation between the two moieties of TDO(C(NH2)2 and SO2); therefore, TDO does not appear to be welldescribed by a zwitterionic structure. Moreover, when the C�Sdistance is increased to 4.1 � (i.e. some 0.5 � beyond the sumof the van der Waals radii of the two atoms), the small chargeseparation vanishes, instead of an increase expected in a zwit-terionic structure. Consistent with this non-zwitterionic charac-ter, the lowest unoccupied molecular orbital (LUMO) of TDO in-dicates a “hole” on the carbon of TDO, that is, a formallyempty 2p orbital corresponding to a singlet carbenoid struc-ture. A comparison of C�S bond lengths in TDO, methanethiol(featuring a well-defined s C�S bond), and thioformaldehyde(featuring a well-defined C�S double bond), as well as of corre-sponding electron densities, reveals that the C�S bond in thio-urea dioxide is significantly longer/weaker than a normal C�Ssingle bond.

In thiourea trioxide the C�N bonds are virtually equivalent(Table 1) and are much shorter than the typical C�N bond(1.470 �). The C�S bond (1.815 �) is slightly shorter than inTDO. Interestingly, the C�S bond in the N-methyl derivative ofthiourea dioxide is shorter than in TDO, but double methyla-tion of thiourea increases the C�S bond both in dioxide andtrioxide.

The structures of di- and trioxides of unsubstituted thioureaare stabilized by intermolecular hydrogen bonds. The decisiverole of hydrogen bonds may partly be related to the fact thattetramethylthiourea dioxide has not been yet prepared in solidstate.[13] Hydrogen bonds strongly influence the density of thi-

Figure 3. Redox isomers of TDO.

Figure 4. Carbenoid structureof TDO.

Table 1. Selected bond lengths [�] of some thiourea dioxides and trioxides.

C�S S�O(1) S�O(2) S�O(3) N(1)�C(1) N(2)�C(1) Reference

(NH2)2CSO2 1.867 1.496 1.496 N.A.[c] 1.296 N.A. [42]N(2)HCH3N(1)H2CSO2·H2O[a] 1.86 1.499 1.471 N.A. 1.293 1.307 [48](NHCH3)2C(1)SO2 1.880 1.479 1.476 N.A. 1.303 1.304 [44](NH2)2CSO3 1.815 1.446 1.431 1.439 1.298 1.297 [28](NHCH3)2C(1)SO3·H2O[b] 1.82 1.433 1.439 1.441 1.290 1.308 [48]

[a] Longer bond with sulfur atom forms oxygen atom which forms a bond with water. [b] Atom O(2) forms a bond with water. [c] N.A. = not applicable.

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ourea oxides as well : the density of N,N’-dimethylthiourea di-oxide (1.496 g cm�3)[44] is much lower than that recorded forthiourea di- (1.70 g cm�3)[42] and trioxide (1.948 g cm�3),[28]

which is probably a consequence of the absence of extensivehydrogen bonding in the first compound.

As mentioned above, many researchers and even suppliersgenerally use the term “aminoiminomethanesulfinic acid”(AIMSA), instead of thiourea dioxide. X-ray studies[40–42] showthat for the substance in the solid state it is an incorrect name.In aqueous solutions, however, AIMSA is the more stable form,that is, tautomerism of TDO into AIMSA proceeds after dissolv-ing the solid material. The first quantum chemical calculationsof this tautomerism, by Makarov and Kudrik,[47] suggested anintermolecular mechanism. Later, intramolecular tautomerismwas found to be feasible as well.[46] It is worth noting thatsupramolecular arrangements lead to stabilization of TDO tau-tomer with respect to AIMSA, in contrast to the situation forisolated molecules in vacuo. This observation is consistent withthe fact that crystallization has so far yielded only the TDO tau-tomer and never AIMSA. Furthermore, all other thiourea diox-ides also crystallize in the form of analogues of TDO, but notin the form of the OH acid (Table 1), while in diluted solutionsand in the absence of strongly interacting hydrogen-bondingpartners the AIMSA tautomer may also play an importantrole.[46] Striking kinetic evidence of tautomerism in aqueous so-lution and the remarkable reactivity difference of the twotautomers will be discussed later.

Stability and Reactivity

Simultaneous TG–DTG–DSC measurements (TG = thermog-ravimetry, DTG = derivative thermogravimetry, DSC = differen-tial scanning calorimetry) showed[9a, 49] that decomposition ofsolid TDO consists of two stages in which the first exothermicstage starts at 115.0 and ends at 129.0 8C, and the maximumdecomposition rate is reached at 118.0 8C. The first stage of de-composition is accompanied by formation of SO2(g).Equation (8) is suggested to account for the production of SO2

from TDO.

2ðNH2Þ2CSO2ðsÞ ! 2ðNH2Þ2COðsÞ þ SðsÞ þ SO2ðgÞ ð8Þ

Excellent agreement exists between the experimentallymeasured enthalpy and the theoretical value calculated fromEquation (8). The decomposition enthalpy of thiourea dioxidederived from the DSC curve equals �50.67 kJ mol�1, whereasthe one calculated from Equation (8) by using formation en-thalpies from literature is �50.01 kJ mol�1.[49a] The second stageof thiourea dioxide decomposition is governed by continuousmelting, vaporization, and decomposition of urea producedfrom the first stage.

In contrast to the exothermic decomposition of TDO, de-composition of solid thiourea trioxide is a strongly endother-mic process, followed by three smaller stages.[49a] The first pro-cess (between 107.0 and 140.0 8C) corresponds to the forma-tion of urea and sulfur dioxide from thiourea trioxide [Eq. (9)] .The three small endothermic processes, with peak tempera-

tures at 157.5, 229.3, and 282.7 8C, result from the continuousmelting, vaporization, and decomposition of urea.

ðNH2Þ2CSO3ðsÞ ! ðNH2Þ2COðsÞ þ SO2ðgÞ ð9Þ

Data on the solid-phase decomposition of thiourea dioxidehave been used by Partal and co-workers,[9a] who studiedmodification of bitumen with TDO. They have shown that asa result of the formation of new chemical compounds, mostprobably by means of reactions between products from thiour-ea dioxide thermal decomposition and some highly polar bitu-men molecules, the permanent deformation resistance of bitu-men at high temperature is enhanced. On the other hand, thi-ourea dioxide addition improves bitumen’s flexibility at low in-service temperatures, and consequently its resistance to ther-mal cracking under loading. As a conclusion, thiourea dioxidecan be considered as a promising modifying agent.

Decomposition of thiourea oxides in aqueous solutionsstrongly depends on pH and on the presence of dioxygen. Allof them are significantly less stable in alkaline solutions than inneutral or acidic conditions. On heating in glacial acetic acid,TDO decomposes to give formamidine acetate and sulfur diox-ide.[24] The corresponding ureas are the only nitrogen-contain-ing products of thiourea, N-methylthiourea, and N,N’-dime-thylthiourea dioxides in strongly alkaline solutions.[50] In less al-kaline media (pH 10) cyanamides as well as ammonia are alsoformed[22b] (ammonia is formed when thiourea trioxide decom-poses in weakly acidic media,[28] as well). Under similar condi-tions (pH around 10), thiourea trioxide gives melamine as wellas cyanoguanidine.[22b] In contrast to dioxide, decomposition ofthiourea trioxide at pH 13–14 is accompanied mainly by forma-tion of cyanamide.[22b] Trioxide is assumed to be much morestable than dioxide in solution, but no experimental evidenceof this assumption has been provided so far.[22b] In a compara-tive study on the stability of TDO and TTO at pH 3–9 by Gaoand co-workers,[39] it was found that in acidic solutions (pH 3–7) TDO is more stable than TTO. Thus, at pH 3.0 the rate con-stants of decomposition of TDO and TTO at 298 K are found tobe 7.46 � 10�7 and 5.42 � 10�6 s�1, respectively. On the otherhand, as pH increases (above pH 7) TTO becomes graduallymore stable than TDO. Evidently, these observations are ex-plained by differences in acid–base properties of dioxide andtrioxide. The pKa of TDO can be approximately estimated fromthe data on rate constants of the decomposition published inreference [39] and, for strongly alkaline solutions, in refer-ence [50] . This approximation yields a pKa of 8.5 at 298 K. Pre-viously, the values of 8.0[51] and 9.5[46] were reported. Thesecontradictions might be partly explained by complications aris-ing from the tautomerism of TDO to AIMSA in acidic solutions(in alkaline solutions decomposition of TDO proceeds muchfaster than its tautomerism). The corresponding data on forma-tion of aminoiminomethanesulfonic acid from TTO are absent.Unfortunately, pK value of TTO has not been published yet,and it is therefore impossible to compare pK’s of dioxide andtrioxide.

The only comparative study of stability of three dioxides ofthioureas, by Svarovsky and co-workers,[50] has shown that in

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strongly alkaline solutions the dioxide of N,N’-dimethylthioureais much less stable than TDO, and the most stable one is thedioxide of N-methylthiourea. Studies on the relative stability ofthiourea trioxides have not been reported yet.

Unfortunately, in many publications the role of dioxygen inthe decomposition of thiourea dioxide and that of their relatedcompounds is not considered. While especially in syntheticpapers it is not specified whether the reaction was carried outunder inert atmosphere or in air, a precise comparison of dataon aerobic and anaerobic decomposition of thiourea dioxideprovided the first direct experimental evidence of formation ofsulfoxylate SO2

2� (SO2H�) during the course of decompositionof TDO. Svarovsky and co-workers observed that decomposi-tion of TDO in air-saturated solutions is accompanied by for-mation of dithionite, preceded by a well-defined time delay.[50]

On the other hand, without dioxygen, dithionite does notappear at all. Dithionite is accumulated under anaerobic condi-tions in the presence of potassium superoxide KO2 or hydro-gen peroxide. The authors have concluded that under aerobicconditions dithionite is formed by sequence of reactionsgiven in Equations (10)–(17) [in Eq. (15) and (16), O� is thedeprotonated form of hydroxyl radical] .

NH2ðNHÞCSO2� þ H2O! SO2H� þ OCðNH2Þ2 ð10Þ

SO22� þ O2 ! SO2

� þ O2� ð11Þ

SO2� þ O2 ! SO2 þ O2

� ð12Þ

SO22� þ O2

� ! SO2� þ O2

2�ðHO2�Þ ð13Þ

SO2� þ O2

� ! SO2 þ O22�ðHO2

�Þ ð14Þ

SO22� þ HO2

� ! SO2� þ O� þ OH� ð15Þ

SO2� þ HO2

� ! SO2 þ O� þ OH� ð16Þ

2 SO2� $ S2O4

2� ð17Þ

N,N’-Dimethylthiourea and N-methylthiourea dioxides pro-duce dithionite under aerobic conditions as well.[50] These ob-servations show that, unlike previously assumed, the sulfur di-oxide anion radical, SO2

� , is not a primary product of thioureadioxide decomposition.[52]

Interestingly, dioxygen influences also the yield of ZnSduring the reaction between zinc salts and thiourea dioxide inslightly acidic solutions.[4a] Davies and co-workers[4a] reportedlower yields of ZnS from precipitation under anaerobic condi-tions compared to aerobic ones, presumably due to the forma-tion of dithionite in presence of dioxygen. They, however, as-sumed that the sulfur dioxide anion radical is formed directlyfrom thiourea dioxide as a result of homolytic C�S bond cleav-age. If it is so, then under anaerobic conditions formation of di-thionite during the course of the decomposition of TDO wouldalso be observed due to the dimerization reaction of SO2C

� rad-ical [see Eq. (17)] . Therefore, we propose that a more plausibleexplanation for formation of dithionite is a reaction betweensulfoxylate and dioxygen. Subsequent production of sulfidethen results from the well-known disproportionation of di-

thionite under acidic conditions.[2] Sulfoxylate, or more precise-ly sulfoxylic acid, is also unstable in acidic solutions, but, seem-ingly, it produces less sulfide during its decomposition than di-thionite does. Interestingly, these authors have also observedevolution of gas (but not sulfurous waste gases) during theearly stage of precipitation process. The most plausible explan-ation of this observation is direct formation of dioxygen fromthiourea dioxide. Indeed, earlier Burgess and co-workers foundthat TDO decomposes into thiourea, urea (2:3 ratio), and di-oxygen, in refluxing anhydrous acetonitrile with 98 % conver-sion.[53] Later Kis and co-workers[46] provided computational evi-dence that this process is also feasible in aqueous solution.The ability to produce oxygen is easier to explain via theAIMSA tautomer, the potential energy surface of which in thecritical regions (O�O distance between 1.3 and 1.7 �) lies100 kcal mol�1 below that of TDO. A significant difference in re-activity between the two tautomers is traceable to the oxygen-bound proton in AIMSA, which allows partial stabilization ofa peroxide S-O-O-H intermediate at an O�O distance of 1.5 �in AIMSA.

Recently the first kinetic evidence of tautomerism of TDO inacidic aqueous solutions and a dramatic difference in reactivityof two tautomers (TDO and AIMSA) were shown in the reduc-tion of chlorine dioxide.[31a] A strong influence of the age ofTDO stock solution (pH 2.5) on the rate of reaction was report-ed; the greater the age of the stock solution, the faster the re-action proceeds. Simultaneous UV/Vis data proved that TDOdoes not decompose in the time interval studied. Experimentsinvolving addition of formaldehyde, which reacts with possibledecomposition products of TDO—sulfoxylate and sulfite—alsoshowed that the aging phenomenon cannot be explained byspontaneous decomposition of TDO. A plausible explanation isa slow but steady tautomerism of TDO into AIMSA, with thesecond tautomer being more reactive towards chlorine dioxidethan the first one. Thus, aging [not only in alkaline solutions—see Eq. (10), but in acidic conditions, too] is a very importantfactor in elucidating the kinetics and mechanism of any reac-tions of TDO in aqueous solutions, due to the slow appearanceof AIMSA. The difference in reactivity of the two tautomersmay well encompass further fine mechanistic details. Theaging effect mentioned above should also be taken into ac-count in the studies of oxidation of thiourea, since in such pro-cesses thiourea dioxide is one of its important products or in-termediates. It should be noted that aging effect can be ex-plained not only by formation of AIMSA, but also an initial for-mation of TDO oligomers in aqueous solution to be differentfrom that of found in solid state. Indeed, recent investigationsof TDO in aqueous solutions by DFT, UV, and Ramanspectroscopy showed that when TDO is dissolved in water itsmolecular structure changes significantly.[31b]

Numerous studies have been devoted to the reactions ofthioureas[13, 54] or thiourea oxides[10a,b,d, 55] with halogens andoxyhalogen compounds. The reactions of oxyhalogens (chlor-ite, chlorine dioxide, bromate, bromite, iodate) with organosul-fur compounds are usually a rich source for the generation ofexotic dynamical phenomena. Very often kinetic models with25 or more reactions are proposed, but even these large sets

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of reactions are unable to explain quantitatively the experi-mental behavior observed. Simoyi and co-workers studied re-actions of different thioureas and their oxides with chlorine-,bromine-, and iodine-containing compounds mostly in acidicaqueous solutions.[13, 54b, 55] Interestingly, they observed theaging effect in the reaction of thiourea trioxide and iodine,[55]

attributing it exclusively to the decomposition of thiourea tri-oxide to sulfite, which then rapidly reacts with iodine. Indeed,the addition of formaldehyde (reacting with sulfite) decreasesthe rate of reaction. However, the aging effect was observedeven under overwhelming excess of formaldehyde. It is there-fore reasonable to assume that a possible rearrangement ofthiourea trioxide takes place similarly to that was observed incase of aqueous acidic TDO solution. For thiourea dioxide thecorresponding effect has not been noted, seemingly due tothe relatively fast direct reaction between thiourea dioxide andiodine.

Interestingly, iodine has been used as a catalyst of reductionof sulfoxides by TDO.[56] Earlier attempts to reduce sulfoxidesunder two-phase conditions using TDO and hexadecyltributyl-phosphonium bromide as a phase-transfer catalyst were un-successful, though sulfimines and disulfides can be reduced tothe corresponding sulfides and thiols under these condi-tions.[57] The properties of TDO as a convenient reducing agentin phase-transfer catalytic processes were also used by Comas-seto and co-workers[58] for the preparation of a number ofcompounds of sulfur, selenium, and tellurium.

The peculiarities of TDO structure, namely, its ability to formhydrogen bonds, have been successfully used in the creationof new effective organocatalysts. In general, thiourea deriva-tives have become a subject of considerable interest fordesign of different catalysts.[59] The presence of two moreoxygen atoms in TDO may possibly be responsible for itshigher catalytic activity as compared to that of thiourea and itcan promote several other transformations in a similar fash-ion.[6e] The exact mechanisms of the reactions catalyzed by thi-ourea dioxide are in most cases still unknown; the proposedmechanisms involve the activation by means of hydrogenbonding between TDO and substrates, as exemplified for thesynthesis of coumarin in Scheme 2:[6e]

Thiourea dioxide was used as organocatalyst in the synthesisof heterocyclic functionalized coumarins, derivatives of dipyrro-methanes[6e] and carbonyl compounds;[6f] naphthopyran deriva-tives;[6d] structurally diverse dihydropyrido[2,3-d]pyrimidine-2,4-diones;[6c] sulfoxides;[6a] 3,4-dihydropyrimidinones;[6b] andpyrano[4,3-b]pyran derivatives.[6g] Thiourea dioxide is found tobe insoluble in various organic solvents and therefore at theend of the reaction, products can be separated by extractionand the recovered catalyst can be used several times witha consistent catalytic activity.

In synthesis of 3,4-dihydropyrimidinones[6b] the host–guestcomplexes between polyethylene glycol and thiourea dioxide(PEG-TDO) prepared by co-crystallization method and bychemical reaction were used as a catalyst. The correspondingpoly(ethylene glycol)–thiourea complexes (PEG–thiourea) werefound to be unreactive and no reaction occurred under similarreaction conditions.

The dual activation approaches via using combined organo-catalysis and metal catalysis were used for the hydrolysis ofimines. Kumar and co-workers have observed a promotingeffect of thiourea dioxide in the cobalt(II)–phthalocyanine-cata-lyzed hydrolysis of imines to the corresponding carbonyl com-pounds and amines under mild conditions.[60] In the absenceof TDO the reaction does not proceed and unreacted imine isrecovered at the end. One of the probable mechanisms in-volves dual activation of the C=N bond of imine and watermolecules by the metal cation and thiourea dioxide throughhydrogen bonding. This nonbonding association activates thewater nucleophile towards the attack on the imine bond(Scheme 3).

The protocol developed is advantageous in several aspects,such as it does not require strong acidic or basic conditions,the catalyst is recyclable and it affords excellent product yieldsin short reaction times. However, in contrast to thiourea-cata-lyzed reactions, the mechanistic features of TDO-catalyzed re-actions have been much less studied. Thiourea trioxide canalso be a promising organocatalyst, as it has strong hydrogenbonds. In this context further studies are likely to unravel morediverse applications of thiourea oxides in organocatalysis andto provide additional proofs for the exact mechanisms where-by these phenomena occur.

The other field in which hydrogen bonds play a very impor-tant role is supramolecular chemistry and, in particular, anionreceptor chemistry. The urea and thiourea functional groupsare among the most popular binding motifs employed in thedesign of neutral anion-binding receptors.[61] The combination

Scheme 2. TDO catalysis for coumarin synthesis.

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of twofold hydrogen-bond donor ability and relatively easysynthetic accessibility accounts for their importance as anion-binding subunits. It should be noted that to the best of ourknowledge, there are no data on applications of thioureaoxides in the receptor chemistry. The ability of these com-pounds to form hydrogen bonds makes them a promising al-ternative possibility for synthesis of new receptors.

In their work[60] Kumar and co-workers have used our earlierdata on the reaction of thiourea dioxide with nitrite in thepresence of cobalt–phthalocyanine.[62] It was shown that reduc-tion of CoII–phthalocyanine to the CoI complex is possible onlyin alkaline solutions. These data confirm the conclusion ofKumar and co-workers[,60] namely, that CoI–phthalocyaninedoes not participate in the synthesis of carbonyl compoundsand amines from imines.

The strong reducing ability of TDO has been applied for thesynthesis of metal complexes in unusually low valencestates.[63–65] The active species of these processes is a productof TDO decomposition—sulfoxylate. The latter is shown to bea convenient reducing agent for the synthesis of highly re-duced iron–tetrasulfophthalocyanine species [FeI(TSPc)]6� in anaqueous solution.[63] Using EPR measurements Mot and co-workers have also shown[64] that thiourea dioxide (sulfoxylate)is capable of producing of formally FeI and Fe0 states at roomtemperature in water. Sulfoxylate can as well produce thesuper-reduced cobalamins (CblI complexes) in alkalinesolutions.[65]

A very strong reducing ability of thiourea dioxide in alkalinesolutions is manifested in the reduction of Cd2+ to themetal.[52] In contrast to TDO, sodium dithionite does notreduce cadmium to the metallic state[52] .

It is also well-known that the Fe2 +/TDO/hydrogen peroxidesystem induces polymerization of various vinyl monomers withflax fibres.[66a] This system has as well been reported to form aneffective redox system capable of initiating grafting of differentvinyl monomers and monomer mixtures onto cottoncellulose.[66b,c] Other effective initiating systems areTDO/KBrO3

[66d, 8b] and TDO/KMnO4.[66e]

The single-electron-transfer/degenerative-chain-transfermediated living radical polymerization of vinyl chloride inwater/tetrahydrofuran catalyzed by thiourea dioxide has been

studied by Percec and co-workers.[8a] They have shown thatpolymerization proceeds only in the presence of NaHCO3 andco-catalyst octyl viologen (OV2+). The catalytic activity of TDOis lower than that of sodium dithionite. The reason is that con-trary to thiourea dioxide, a single-electron-transfer reductant—sulfur dioxide anion radical—is produced by the dissociationof dianion S2O4

2� directly (to form SO2� from sulfoxylate, the

presence of an oxidizing agent is required). The other reasonof relatively low effectiveness of TDO is the possible side reac-tions caused by the sulfoxylate anion—the product of decom-position of thiourea dioxide.[8a] Indeed, sulfoxylate can reduceOV2 + to the neutral octyl viologen, which is an extremelystrong reductant. The formation of OV0 may also mediate sidereactions. The formation of neutral methyl viologen after re-duction of the methyl viologen dication by thiourea dioxide(sulfoxylate) was observed by Makarov and co-workers.[12a]

A series of original papers and reviews has recently beenpublished on the application of thiourea dioxide for reductionof graphene and graphite oxides.[3] The chemical reduction ofgraphene oxide is a promising route towards the large-scaleproduction of graphene for commercial applications.[3c] Cur-rently there is a wide range of reducing agents for grapheneoxide in the literature. Chua and Pumera have grouped reduc-tion methods involving these reducing agents into two cate-gories : reduction methods with “well-supported” mechanismsand reduction methods with “proposed” mechanisms.[3c] Thefirst methods use traditional reductants, and the second meth-ods use those compounds that have been previously appliedas reducing agents in synthetic chemistry. The first group in-cludes borohydrides, lithium aluminium hydride, hydrohalicacids, and sulfur-containing reductants [e.g. , thiourea dioxide,ethanethiol/aluminium chloride and Lawesson’s reagent(2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-di-thione)] . Thiourea dioxide is much cheaper and easier tohandle than most of these reducing agents. The other advant-age is that the reduction with TDO produces common nontox-ic commercial wastes, such as sodium sulfite and urea.[3b] TDOas reductant afforded high-quality chemically reduced gra-phene oxide with a C/O ratio as high as about 16.0, which ishigher than that obtained by using other reducing agents.[3b]

On the basis of earlier studies, in which TDO was success-fully employed for reduction of epoxy and carbonyl group-s[5a,b, 67–69] as well as deoxygenation of N-oxides,[70] Pan and co-workers have suggested a rapid low-temperature syntheticmethod leading to large-scale carboxyl graphene.[3e] The latterwas prepared by selective reduction of epoxy and carbonylgroups on graphene oxide using thiourea dioxide, while car-boxyl groups were left behind. The presence of these remain-ing carboxyl groups may allow these materials to be modifiedfurther, thus extending the scope of applications for graphene.A mechanism for selective reduction of the epoxy and carbon-yl groups on graphene oxide (GO) to form carboxyl grapheneby TDO is proposed (Figure 5). Sulfoxylate ions SO2H� fromTDO (1) attack the carbon atom of the epoxide (6) to convertit into a hydroxyl group (7) through a ring-opening substitu-tion. Subsequently, a condensation cyclization reaction occursto yield compound 8, which quickly rearranges to form the C=

Scheme 3. Imine activation with TDO.

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C bond in 9 and releases SO2. Additionally, sulfoxylate ions alsoattack the carbonyl group attached to GO (10) through a nucle-ophilic addition reaction by releasing one H2O molecule andone SO2 molecule, thus yielding primary and secondary alco-hols (12). Meanwhile, the carboxyl groups in the GO were notreduced by TDO.

The other mechanism of reduction of graphene oxide byTDO was suggested by Ma and co-workers.[3f] They proposedthat the strong reduction capacity of TDO is attributed notuniquely to sulfoxylate ion, but also to the synergistic effect of

its hydrolysis and oxidation products (sulfite and urea) in alka-line aqueous media. Since sulfoxylate is a much more potentreductant, this mechanism can be considered as a lessprobable one.

Thiourea trioxides have received considerably less attentionin chemistry and technology compared to thiourea dioxides.

The only one important field of their application (and, toa lesser extent, of thiourea dioxides) is the synthesis of guani-dines and guanidino acids by reaction with amines or aminoa-cids.[11, 22, 25, 26, 71] N-Hydroxyguanidines were synthesized bytreatment of the corresponding thiourea trioxide with hydrox-ylamine hydrochloride and triethylamine.[72] Treatment of thio-urea trioxides with cyanamide yields the corresponding N-cya-noguanidines.[72] Double guanidinylation and cyclization reac-tion of thiourea dioxide with methyl anthranilates yields 5 H-quinazolino[3,2-a]quinazoline-5,12(6 H)diones.[73] It should benoted that for introduction of the H2N�C=NH moiety from thi-ourea oxide into an amine group, different authors use differ-ent terms—guanidinylation[11a] and formamidination[71a]—oruse different names for the same compound, for example, gua-nidinoacetic acid[22b] and N-formamidineglycine[11b] for theproduct of reaction between glycine and thiourea trioxide (di-oxide). Contrary to dioxides, in which the sulfur-containingpart of the molecule dominates in many practical applications,in trioxides the nitrogen-containing fragment plays the domi-nating role, with the sulfur–oxygen moiety mostly just a leavinggroup with an auxiliary role. Guanidines have long been thefocus of considerable attention as a ubiquitous moiety incor-porated into many drugs with numerous therapeutic applica-tions and biological activities (see, for example, reference-s [71a, 74]) ; other references on applications of guanidines inthe synthesis of drugs can be found elsewhere.[2] The high ba-sicity and the ability to provide two protons that point in ap-proximately the same direction make the guanidinium groupvery important in anion receptor design.[61] Guanidines are alsoknown as effective organocatalysts.[75]

Combinations of guanidines and thioureas as additional hy-drogen-bonding functionalities in the same molecule haveemerged as especially successful catalysts scaffolds allowing toactivate simultaneously nucleophiles by the guanidine andelectrophiles by thiourea.[76]

Thiourea trioxide has been used for guanidinylation of chito-san[11a,d] as shown in Figure 6. Chitosan, a natural nontoxic bio-polymer, has an antimicrobial and antitumor activity.[11a,d, 77–79]

The chemical modifications of chitosan afford a wide range ofderivatives with modified properties for specific applications.[79]

Guanidinylated chitosan was reported to have much better an-tibacterial activity, with minimal inhibitory concentrations inaqueous hydrochloric acid (pH 5.4) four times lower than thoseof chitosan.[11a] The mechanism of this antibacterial activity isunknown, but it has indeed been proposed that adding aminogroups (as in substituting amino by formamidine to obtaina guanidinylated chitosan) would enhance the antibacterialactivity.

The interaction of thiourea oxides with amino acids alsooccurs in the course of inactivation and modification of cyti-dine triphosphate (CTP) synthetase.[80a] Thiourea dioxide was

Figure 5. Proposed mechanism for the reduction of graphene oxide by TDOin alkaline aqueous solution.

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used in chemical modification studies to identify functionallyimportant amino acids in Escherichia coli CTP synthetase. Incu-bations at pH 8.0 led to the irreversible inactivation of theenzyme. The proposed mechanism for inactivation includesa TDO reaction with lysine to form homoarginine. The specifici-ty of TDO for lysine residues indicates that one or more lysinesare most likely involved in CTP synthetase activity. Earlier stud-ies have also shown that thiourea dioxide effectivelyinactivates glutamine synthetase.[80b, c]

Unfortunately, kinetic data on the reactions between thiour-ea oxides and amines are relatively scarce. In the presence ofalkali and air (dioxygen), thiourea dioxide produces dithionite(S2O4

2�) after addition of aliphatic amines (for example, methyl-amine), under aerobic conditions;[81] in the absence of dioxy-gen dithionite does not appear at all. However, in the mixturewith amine the concentration of TDO decreases much fasterthan in the presence of alkali of the same concentration asamine.[81] One can conclude that at the first step thiourea diox-ide rapidly forms a relatively stable intermediate with theamine, which further produces sulfoxylate and, in presence ofdioxygen, dithionite. Indeed, during the course of the reactionof morpholine with N-phenylaminoiminomethanesulfonic acid(N-phenylthiourea trioxide) at room temperature, a transientintermediate was detected by TLC, but it was not characterizedby 1H or 13C NMR spectroscopy.[26] When the reaction was stud-ied by IR spectroscopy, no carbodiimide or cyanamide was ob-served. Therefore, an addition/elimination mechanism was pro-posed involving addition of amine nucleophile to thiourea(substituted thiourea) trioxide to form a tetrahedral intermedi-ate that collapses to product guanidine as shown in Figure 7.

Higher yields of guanidine resulted from the reaction ofmorpholine with phenylthiourea trioxide than that of the cor-responding dioxide,[26b] but a clear explanation of this phenom-enon is still not available. One of the possible reasons mightbe the difference in the decomposition process of dioxide andtrioxide (see above).

Maryanoff and co-workers[26] compared the reactivity of N-phenylthiourea trioxide and another widely employed guanidi-lating agent, S-methylisothiouronium iodide, towards morpho-line. It was determined that the S-trioxide group was replacedabout 15 times faster than the S-methyl group in morpholine.Thus, the advantages mentioned above make the thiourea

oxides very convenient and useful in the synthesis ofguanidines.

Summary and Outlook

In this review we tried to collect new data on the chemistryand applications of thiourea oxides. In the last decades the ap-plication of their precursors, thioureas, in organocatalytic reac-tions and supramolecular chemistry has increased tremendous-ly, with their ability to form strong hydrogen bonds beinga critical point. Since the introduction of two or three oxygenatoms in the thiourea molecule can significantly modify thishydrogen-bonding ability, thiourea oxides may also have goodperspectives of application in the fields mentioned above.Also, one cannot underestimate the strong reducing propertiesof thiourea dioxides and their usage (as well as of thioureamonoxides) as precursors of unusual sulfur-containing species�S(OH)2 and possibly HSOH, as well as the application of thio-urea oxides in the synthesis of guanidines. New kinetic infor-mation on the reactions between thiourea oxides and halo-gen-containing compounds can explain some of the unusualcharacteristics of corresponding reactions of thioureas. Herewe did not discuss the development of traditional and stillvery important fields of application of thiourea dioxide, in par-ticular in the textile and paper industries, since it was reviewedin detail earlier.[2, 82, 83] We hope that thiourea oxides will findtheir well-deserved role on new applications in the near future.

Acknowledgements

This work was supported by a grant from the National NaturalScience Foundation of China(No. 51221462), a grant fromJiangsu province Natural Science Foundation (No. BK20131111),the Fundamental Research Funds for the Central Universities(No. 2013 K05) and PAPD. A.K.H. is grateful for the financialsupport of Chinese–Hungarian cooperative grant no.:K-T�T-CN-1-2012-0030. R.S.-D. thanks the Romanian Ministry for Educa-tion and Research with the support of PCE 488/2012 grant.

Keywords: reactivity · reduction · sulfoxylate · thiourea oxides

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Figure 7. Interaction of thiourea trioxides with amines.

Figure 6. Derivatization of chitosan with thiourea trioxide.

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