View source for Disulfide

{{Short description|Functional group with the chemical structure R–S–S–R′}}
{{dist|Bisulfide}}
{{About|inorganic and organic disulfides|disulfides in proteins|Disulfide (biochemistry)}}

In [[chemistry]], a '''disulfide''' (or '''disulphide''' in [[British English]]) is a compound containing a {{chem2|R\s'''S\sS'''\sR′}} [[functional group]] or the {{chem|S|2|2−}} [[anion]]. In [[inorganic chemistry]], the anion appears in a few rare minerals. Compounds of the form {{chem2|R\sS\sS\sH}} are usually called ''[[persulfide]]s'' instead.

[[Disulfide (biochemistry)|Disulfide bridges]] also appear as a common [[post-translational modification]] in proteins.

==Organic disulfides==
{{Multiple image
| align             = 
| direction         = vertical
| total_width       = 
| image1            = Cystine-from-xtal-Mercury-3D-balls-thin.png
| image2            = Lipoic-acid-from-xtal-3D-bs-17.png
| image3            = Diphenyl-disulfide-from-xtal-3D-balls.png
| caption1          = [[Cystine]], crosslinker in many proteins
| caption2          = [[Lipoic acid]], an enzyme cofactor
| caption3          = [[Diphenyl disulfide]], {{chem2|(C6H5)2S2}}, a common organic disulfide
| alt1              = 
| header            = A selection of organic disulfides
}}

===Structure===
Disulfides have a C–S–S–C [[dihedral angle]] approaching 90°. The S–S bond length is 2.03 Å in [[diphenyl disulfide]],<ref>{{cite journal|doi=10.1107/S0567740869005188 |title=The Crystal Structure of Diphenyl Disulphide |date=1969 |last1=Lee |first1=J. D. |last2=Bryant |first2=M. W. R. |journal=Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry |volume=25 |issue=10 |pages=2094–2101 |bibcode=1969AcCrB..25.2094L }}</ref> similar to that in elemental sulfur.

Disulfides are usually symmetric but they can also be unsymmetric. Symmetrical disulfides are compounds of the formula {{chem2|RSSR}}. Most disulfides encountered in organosulfur chemistry are symmetrical disulfides. '''Unsymmetrical disulfides''' (also called '''heterodisulfides''' or '''mixed disulfides''') are compounds of the formula {{chem2|RSSR'}}. Unsymmetrical disulfide are less common in organic chemistry, but many disulfides in nature are unsymmetrical.  

====Cyclic disulfides====
Disulfides can be components of rings. [[Lipoic acid]], a [[1,2-Dithiolane|1,2-dithiolane]] is a major example. Rings with more than one disulfide usually tend to polymerize.<ref>{{cite journal |doi=10.1016/0040-4020(89)80036-5 |title=Characterization and stability of cyclic disulfides and cyclic dimeric bis(disulfides) |date=1989 |last1=Houk |first1=Janette |last2=Whitesides |first2=George M. |journal=Tetrahedron |volume=45 |pages=91–102 }}</ref>

====Other specialized organic disulfides====
[[Thiuram disulfide]]s, with the formula (R<sub>2</sub>NCSS)<sub>2</sub>, are disulfides but they behave distinctly because of the [[thiocarbonyl]] group.

===Properties===
Disulfide bonds are strong, with a typical [[bond dissociation energy]] of 60&nbsp;kcal/mol (251&nbsp;kJ&nbsp;mol<sup>−1</sup>). However, being about 40% weaker than {{chem2|[[C–C bond|C\sC]]}} and {{chem2|[[Carbon–hydrogen bond|C\sH]]}} bonds, the disulfide bond is often the "weak link" in many molecules. Furthermore, reflecting the [[polarizability]] of divalent sulfur, the {{chem2|S\sS}} bond is susceptible to scission by polar reagents, both [[electrophile]]s and especially [[nucleophile]]s (Nu):<ref>{{cite book|first=R. J.|last=Cremlyn|title=An Introduction to Organosulfur Chemistry|publisher=John Wiley and Sons|location=Chichester|date=1996|isbn=0-471-95512-4}}</ref> <chem display=block>RS-SR + Nu- -> RS-Nu + RS-</chem> 

The disulfide bond is about 2.05&nbsp;[[ångström|Å]] in length, about 0.5&nbsp;Å longer than a {{chem2|C\sC}} bond. Rotation about the {{chem2|S\sS}} axis is subject to a low barrier. Disulfides show a distinct preference for [[dihedral angle]]s approaching 90°. When the angle approaches 0° or 180°, then the disulfide is a significantly better oxidant.

Disulfides where the two R groups are the same are called symmetric, examples being [[diphenyl disulfide]] and [[dimethyl disulfide]]. When the two R groups are not identical, the compound is said to be an asymmetric or mixed disulfide.<ref name=Sevier>{{cite journal | doi = 10.1038/nrm954 |last1=Sevier |first1=C. S. |last2=Kaiser |first2=C. A. | title = Formation and transfer of disulphide bonds in living cells | journal = [[Nature Reviews Molecular Cell Biology]]  | year = 2002 | volume = 3 | issue = 11 | pages = 836–847 | pmid = 12415301|s2cid=2885059 | doi-access = free }}</ref>

Although the [[hydrogenation]] of disulfides is usually not practical, the equilibrium constant for the reaction provides a measure of the standard redox potential for disulfides:
:<chem>RSSR + H2 -> 2 RSH</chem>
This value is about −250&nbsp;mV versus the [[standard hydrogen electrode]] (pH&nbsp;=&nbsp;7). By comparison, the standard reduction potential for [[ferrodoxin]]s is about −430&nbsp;mV.

===Synthesis===
Disulfide bonds are usually formed from the [[oxidation]] of [[thiol]] ({{chem2|\sSH}}) groups, especially in biological contexts.<ref name=Witt>{{cite journal | last = Witt | first = D. | title = Recent developments in disulfide bond formation | journal = [[Synthesis (journal)|Synthesis]] | volume = 2008 | year = 2008 | issue = 16 | pages = 2491–2509 | doi = 10.1055/s-2008-1067188}}</ref> The transformation is depicted as follows:
:<chem>2 RSH <=> RS-SR + 2 H+ + 2 e-</chem>
A variety of oxidants participate in this reaction including oxygen and [[hydrogen peroxide]]. Such reactions are thought to proceed via [[sulfenic acid]] intermediates. In the laboratory, [[iodine]] in the presence of base is commonly employed to oxidize thiols to disulfides. Several metals, such as copper(II) and iron(III) [[metal complex|complex]]es affect this reaction.<ref>{{cite journal |last1=Kreitman |first1=Gal Y. |title=Copper(II)-Mediated Hydrogen Sulfide and Thiol Oxidation to Disulfides and Organic Polysulfanes and Their Reductive Cleavage in Wine: Mechanistic Elucidation and Potential Applications |journal=Journal of Agricultural and Food Chemistry |date=March 5, 2017 |volume=65 |issue=12 |pages=2564–2571 |doi=10.1021/acs.jafc.6b05418 |pmid=28260381 |bibcode=2017JAFC...65.2564K |url=https://pubs.acs.org/doi/10.1021/acs.jafc.6b05418 |access-date=31 May 2021|url-access=subscription }}</ref> Alternatively, disulfide bonds in proteins often formed by [[thiol-disulfide exchange]]:
: <chem>RS-SR + R'SH <=> R'S-SR + RSH</chem>
Such reactions are mediated by enzymes in some cases and in other cases are under equilibrium control, especially in the presence of a catalytic amount of base.

The [[alkylation]] of alkali metal di- and [[polysulfide]]s gives disulfides. "Thiokol" polymers arise when [[sodium polysulfide]] is treated with an alkyl dihalide. In the converse reaction, carbanionic reagents react with elemental sulfur to afford mixtures of the thioether, disulfide, and higher polysulfides. These reactions are often unselective but can be optimized for specific applications.

===Synthesis of unsymmetrical disulfides (heterodisulfides)===
Many specialized methods have been developed for forming unsymmetrical disulfides. Reagents that deliver the equivalent of "{{chem2|RS+}}" react with thiols to give asymmetrical disulfides:<ref name=Witt/>
: <chem>RSH + R'SNR''_2 -> RS-SR' + HNR''_2</chem>
where {{chem2|R{{pprime}}2N}} is the [[phthalimide|phthalimido]] group.
[[Bunte salt]]s, derivatives of the type {{chem2|RSSO3(-)Na+}}are also used to generate unsymmetrical disulfides:<ref>{{cite journal|title=Sulfide Synthesis in Preparation of Unsymmetrical Dialkyl Disulfides: Sec-butyl Isopropyl Disulfide|journal=Org. Synth.|year=1978|volume=58|page=147|doi=10.15227/orgsyn.058.0147|author1=M. E. Alonso |author2=H. Aragona }}</ref>
:<chem>Na[O3S2R] + NaSR' -> RSSR' + Na2SO3</chem>

=== Reactions ===
The most important aspect of disulfide bonds is their scission, as the {{chem2|S\sS}} bond is usually the weakest bond in an organic molecule (missing citation). Many specialized [[organic reaction]]s have been developed to cleave the bond. 

A variety of reductants reduce disulfides to [[thiols]]. Hydride agents are typical reagents, and a common laboratory demonstration "uncooks" eggs with [[sodium borohydride]].<ref>Hervé This. Can a cooked egg white be uncooked? The Chemical Intelligencer (Springer Verlag), 1996 (14), 51.  </ref> Alkali metals effect the same reaction more aggressively: <chem display=block>RS-SR + 2 Na -> 2 NaSR,</chem> followed by protonation of the resulting metal thiolate: <chem display=block>NaSR + HCl -> HSR + NaCl</chem>In biochemistry labwork, thiols such as β-[[mercaptoethanol]] (β-ME) or [[dithiothreitol]] (DTT) serve as reductants through [[#Thiol-disulfide exchange|thiol-disulfide exchange]]. The thiol reagents are used in excess to drive the equilibrium to the right: <chem display="block">RS-SR + 2 HOCH2CH2SH <=> HOCH2CH2S-SCH2CH2OH + 2 RSH</chem>
The reductant [[TCEP|tris(2-carboxyethyl)phosphine]] (TCEP) is useful, beside being odorless compared to β-ME and DTT, because it is selective, working at both alkaline and acidic conditions (unlike DTT), is more hydrophilic and more resistant to oxidation in air. Furthermore, it is often not needed to remove TCEP before modification of protein thiols.<ref name="FT-242214">[http://www.interchim.fr/ft/2/242214.pdf TCEP technical information], from [[Interchim]]</ref>

In Zincke cleavage, halogens oxidize disulfides to a [[sulfenyl halide]]:<ref>{{multiref|
{{OrgSynth | first = Max H. | last = Hubacher | year = 1935 | title = ''o''-Nitrophenylsulfur Chloride| volume= 15|
doi= 10.15227/orgsyn.015.00452 | page = 45}}
|{{OrgSynth | first1 = Irwin B. | last1 = Douglass | first2 = Richard V. | last2 = Norton | year = 1960| title = Methanesulfinyl Chloride| volume = 40 | page = 62| doi=10.15227/orgsyn.040.0062}}
}}</ref><chem display="block">ArSSAr  +  Cl2  ->  2 ArSCl</chem>More unusually, oxidation of disulfides gives first [[thiosulfinate]]s and then [[thiosulfonate]]s:<ref name="review">{{cite journal|title=Thiosulfonates: Synthesis, Reactions and Practical Applications|author=Nikolai S. Zefirov, Nikolai V. Zyk, Elena K. Beloglazkina, Andrei G. Kutateladze|journal=Sulfur Reports|year=1993|volume=14|pages=223–240|doi=10.1080/01961779308055018}}</ref>
:RSSR&nbsp;+ [O]&nbsp;→ RS(=O)SR
:RS(=O)SR&nbsp;+ [O]&nbsp;→ RS(=O)<sub>2</sub>SR

====Thiol-disulfide exchange====
In thiol–disulfide exchange, a [[thiol]]ate group {{chem2|\sS-}} displaces one [[sulfur]] [[atom]] in a disulfide bond {{chem2|\sS\sS\s}}. The original disulfide bond is broken, and its other sulfur atom is released as a new thiolate, carrying away the negative charge. Meanwhile, a new disulfide bond forms between the attacking thiolate and the original sulfur atom.<ref>{{cite book | last = Gilbert | first = H. F. | year = 1990 | chapter = Molecular and Cellular Aspects of Thiol–Disulfide Exchange | volume = 63 | pages = 69–172 | pmid = 2407068 | doi = 10.1002/9780470123096.ch2| title = Advances in Enzymology and Related Areas of Molecular Biology | isbn = 978-0-470-12309-6 }}</ref><ref>{{cite book | last = Gilbert | first = H. F. | year = 1995 | doi = 10.1016/0076-6879(95)51107-5 | chapter = Thiol/disulfide exchange equilibria and disulfide bond stability | title = Biothiols, Part A: Monothiols and Dithiols, Protein Thiols, and Thiyl Radicals | series = [[Methods in Enzymology]] | volume = 251 | pages = 8–28 | pmid=7651233| isbn = 978-0-12-182152-4 }}</ref>
[[File:Thiol disulfide exchange.png|center|frame|Thiol–disulfide exchange showing the linear intermediate in which the charge is shared among the three sulfur atoms. The thiolate group (shown in red) attacks a sulfur atom (shown in blue) of the disulfide bond, displacing the other sulfur atom (shown in green) and forming a new disulfide bond.]]
Thiolates, not thiols, attack disulfide bonds. Hence, thiol–disulfide exchange is inhibited at low [[pH]] (typically, below 8) where the protonated thiol form is favored relative to the deprotonated thiolate form. (The [[pKa|p''K''<sub>a</sub>]] of a typical thiol group is roughly 8.3, but can vary due to its environment.) Thiol-disulfide exchange is an important process for the formation of the correct [[Disulfide (biochemistry)|disulfide bridges]] in proteins and to keep cysteine from unwanted oxidation during lab experiments.

=== Nomenclature and misnomers ===
{{Multiple image
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| image1            = Carbon-disulfide-3D-balls.png
| alt1              = 
| caption1          = CS<sub>2</sub>
| image2            = Molybdenite-3D-balls.png
| caption2          = MoS<sub>2</sub>
}}

[[Thiosulfoxide]]s are isomeric with disulfides, having the second sulfur branching from the first and not partaking in a continuous chain, i.e. >S=S rather than −S−S−.

Compounds with three sulfur atoms, such as CH<sub>3</sub>S−S−SCH<sub>3</sub>, are called trisulfides. More extended species are well known, especially in rings.

Disulfide is also used to refer to compounds that contain two sulfide (S<sup>2−</sup>) centers. The compound [[carbon disulfide]], CS<sub>2</sub> is described with the structural formula i.e. S=C=S. This molecule is not a disulfide in the sense that it lacks a S-S bond. Similarly, [[molybdenum disulfide]], MoS<sub>2</sub>, is not a disulfide in the sense again that its sulfur atoms are not linked.

Disulfide bonds are analogous but more common than related [[peroxide]], [[thioselenide]], and [[diselenide]] bonds. Intermediate compounds of these also exist, for example thioperoxides such as [[hydrogen thioperoxide]], have the formula R<sup>1</sup>OSR<sup>2</sup> (equivalently R<sup>2</sup>SOR<sup>1</sup>). These are isomeric to [[sulfoxide]]s in a similar manner to the above; i.e. >S=O rather than −S−O−.

==Inorganic disulfides==
{{Multiple image
| align             = 
| direction         = vertical
| total_width       = 
| image1            = Pyrite-unit-cell-3D-balls.png
| image2            = Disulfur-dichloride-3D-balls.png
| caption1          = [[Pyrite]], {{chem2|FeS2}}, "fool's gold".  Color code: yellow = S, violet = Fe
| caption2          = [[Disulfur dichloride]], {{chem2|S2Cl2}}, a common industrial chemical
| alt1              = 
| header            = A selection of disulfides
}}

The disulfide [[anion]] is {{chem|S|2|2−}}, or <sup>−</sup>S−S<sup>−</sup>. In disulfide, [[sulfur]] exists in the reduced state with oxidation number −1. Its electron configuration then resembles that of a [[chlorine]] atom. It thus tends to form a covalent bond with another S<sup>−</sup> center to form {{chem|S|2|2−}} group, similar to elemental chlorine existing as the diatomic Cl<sub>2</sub>. [[Oxygen]] may also behave similarly, e.g. in [[peroxide]]s such as H<sub>2</sub>O<sub>2</sub>. Examples of inorganic disulfides include:
* [[Hydrogen disulfide]] (S<sub>2</sub>H<sub>2</sub>), the simplest inorganic disulfide
* [[Disulfur dichloride]] (S<sub>2</sub>Cl<sub>2</sub>), a distillable liquid.
* [[Iron]] disulfide (FeS<sub>2</sub>), or [[pyrite]].

==Applications==
Aside from the [[Disulfide (biochemistry)|major role in biology]], disulfides are found in rubber that has been vulcanized with sulfur. The [[vulcanization]] of [[Natural rubber|rubber]] results in crosslinking groups which consist of disulfide (and polysulfide) bonds; in analogy to the role of disulfides in proteins, the S−S linkages in rubber strongly affect the stability and [[rheology]] of the material.<ref name=":0">{{Cite journal |last1=Akiba |first1=M. |last2=Hashim |first2=A.S. |date=1997 |title=Vulcanization and crosslinking in elastomers |url=https://www.sciencedirect.com/science/article/pii/S0079670096000159 |journal=[[Progress in Polymer Science]] |volume=22 |issue=3 |pages=475–521 |doi=10.1016/S0079-6700(96)00015-9 |via=[[Elsevier Science Direct]]|url-access=subscription }}</ref> Although the exact mechanism underlying the vulcanization process is not entirely understood (as multiple reaction pathways are present but the predominant one is unknown), it has been extensively shown that the extent to which the process is allowed to proceed determines the physical properties of the resulting rubber—namely, a greater degree of crosslinking corresponds to a stronger and more rigid material.<ref name=":0" /><ref name=":1">{{Cite journal |last1=Mutlu |first1=Hatice |last2=Theato |first2=Patrick |date=2020 |title=Making the Best of Polymers with Sulfur–Nitrogen Bonds: From Sources to Innovative Materials |journal=[[Macromolecular Rapid Communications]] |volume=41 |issue=13 |article-number=2000181 |doi=10.1002/marc.202000181 |pmid=32462759 |s2cid=218975603|doi-access=free }}</ref> The current conventional methods of rubber manufacturing are typically irreversible, as the unregulated reaction mechanisms can result in complex networks of sulfide linkages; as such, rubber is considered to be a [[Thermosetting polymer|thermoset]] material.<ref name=":0" /><ref name=":2">{{Cite journal |last1=Bin Rusayyis |first1=Mohammed |last2=Torkelson |first2=John |date=2021 |title=Reprocessable covalent adaptable networks with excellent elevated-temperature creep resistance: facilitation by dynamic, dissociative bis(hindered amino) disulfide bonds |url=https://pubs.rsc.org/en/content/articlelanding/2021/PY/D1PY00187F |journal=[[Polymer Chemistry (journal)|Polymer Chemistry]] |volume=12 |issue=18 |pages=2760–2771 |doi=10.1039/D1PY00187F |s2cid=234925061|url-access=subscription }}</ref>

==See also==
* {{anl|Thiosulfinate}}
* Diselenides in [[organoselenium chemistry]]
* [[Covalent adaptable network]]

==References==
{{Reflist|30em}}

==External links==
* {{Commonscatinline|Disulfides}}

{{Disulfides}}
{{Functional group}}

{{DEFAULTSORT:Disulfide Bond}}
[[Category:Organic disulfides| ]]
[[Category:Sulfur]]
[[Category:Functional groups]]