Alcohols, Epoxides and Ethers
Thiols And Thioethers
Last updated: June 1st, 2020 |
Thiols and Thioethers: Properties and Key Reactions
Here’s a summary of today’s post on thiols:
Table of Contents
- Thiols and Thioethers
- First Things First: Thiols Smell Bad
- Thiols Are More Acidic Than Alcohols
- Sulfur: Less Basic, More Nucleophilic Than Oxygen
- Common Reactions of RS(–) : SN2 Reactions With Alkyl Halides
- Key Differences Between Thiols and Alcohols
- Summary: Thiols and Thioethers
- Quiz Yourself!
- (Advanced) References and Further Reading
One of the most powerful insights from learning the periodic table is the fact elements in the same period (column) have similar chemical properties.
- Alkali metals (Li, Na, K…) all shed an electron relatively easily to form monovalent cations
- Halogens (F, Cl, Br) all gain an electron relatively easily to form halide ions.
- Noble gases (He, Ne, Ar, Kr…) tend to be chemically inert.
So how does what we’ve learned about the reactivity of oxygen (O) based functional groups translate to its heavier cousins sulfur (S) , selenium (Se) and tellurium (Te)?
Specifically, how does the chemistry of alcohols (ROH) and ethers (ROR) compare with the chemistry of thiols (RSH) and thioethers [aka sulfides] (RSR)?.
Great question! That’s the topic of today’s post, specifically thiols and thioethers. We won’t really talk about selenium chemistry beyond briefly mentioning its acidity, and we definitely won’t go anywhere near tellurium chemistry, following Wöhler’s advice on diethyl tellurium that “its obnoxious and persistent smell is connected to unpleasantness, which one wouldn’t like to endure a second time“, and that “the smell is so persistent, that one has to avoid social life for several months in order not to molest other people“.
Let’s start with what’s similar between alcohols/thiols, ethers/thioethers, and then move to what’s vastly different.
Open a textbook that discusses thiols and one of the first things they’ll mention is their vile stench. We wouldn’t want to break with this honourable tradition here at MOC.
Hydrogen sulfide (H2S) is responsible for the smell of rotten eggs and bad breath, among other unpleasant things. Thiols contribute to the smell of skunks and “skunky” beer.
During my time in grad school one of the world’s leading organosulfur chemists had a lab across the hall. These were not people you wanted to be downwind from. Imagine getting on the city bus and having the people next to you get up from their seats and move down to the other end. Those stories were not uncommon from the people in that lab.
BTW: the sulfur chemists’ best friend is bleach, which oxidizes stinky thiols to relatively odourless sulfoxides (see #5, below).
We’ve seen that alcohols are relatively acidic (pKa’s of about 16-17). Thiols are more acidic than alcohols by an average of about 5 pKa units or so ( pKa of about 11 for the thiol pictured below). Remember that pKa is logarithmic, so that means they’re about 105 times more acidic.
Why might that be?
When understanding acidity trends it greatly helps to think about the stability of the conjugate base
Recall that acidity will be increased by any factor which stabilizes the conjugate base. [Since acid-base reactions are equilibria, if we stabilize the product (conjugate base) we therefore make the equilibrium where the starting material (acid) loses a proton more favourable, increasing Ka. In other words, we increase the acidity.]
In the case of sulfur, the negative charge will be borne on a larger atom (sulfur > oxygen) and that negative charge dispersed over a greater volume. Greater volume = more diffuse charge = greater stability. Note the greater pKa of the molecule pictured above (about 10-11).
The same holds true for selenium, which has an even larger atomic radius. I can’t find a pKa value for propaneselenol but would estimate it to be about 7-8. [If someone has a better number, please let me know!]
A corollary of the fact that the conjugate base is more stable is that thiolates [the conjugate bases of thiols] are weaker bases than alkoxides. [“The stronger the acid, the weaker the conjugate base“].
Remember how alkoxides [RO–] can act as nucleophiles in SN2 reactions as well as the base in elimination (E2) reactions? With thiolates [RS–], E2 reactions aren’t an issue. The weaker basicity of thiolates means that only SN2 reactions occur with alkyl halides.
Thiols are more nucleophilic than alcohols, and thiolates are more nucleophilic than alkoxides. Since nucleophilicity is measured by reaction rate, that means that these sulfur nucleophiles tend to react faster with typical electrophiles (like alkyl halides) than their oxygen-based cousins.
Why? As we’ve discussed before, the lower electronegativity of sulfur (relative to oxygen) means that its pairs of electrons are held onto less tightly than oxygen, making them more readily available for donation to electrophiles (like alkyl halides). This trend continues as we descend a column of the periodic table, so in general, nucleophilicity increases in this direction as well (i.e. RSe– is even more nucleophilic than RS– ).
We’ve seen that one of the most important reactions to form ethers is the Williamson ether synthesis. Here’s a textbook example of the sulfur analogue of this reaction: substitution of alkyl halides with thiolates to form thioethers (also known as sulfides).
This process resembles the Williamson to a tee. First, a strong base deprotonates the thiol (we use NaH here, but many other bases could also be used). Secondly, we add an alkyl halide, and an SN2 reaction results in formation of S-C and breakage of C-Br with inversion of stereochemistry.
As mentioned above, note that if we were using an alkoxide, we’d have to worry about the E2 reaction competing with the SN2. With thiolates, it’s not an issue due to their decreased basicity.
Since it comes up so much in exams, the intramolecular version is important to note. Note that we’re still forming C–S here and breaking a carbon-halide bond. Don’t forget that inversion occurs on the stereocenter on the secondary carbon!
In previous posts we saw that primary alcohols are oxidized to aldehydes and secondary alcohols are oxidized to ketones.
This doesn’t work with thiols! Thiols aren’t oxidized to π bonds in the same way. The C–S π bond is actually quite weak due to poor orbital overlap. [note below]
Instead, two different types of oxidation reactions occur with thiols.
- Thiols can be oxidized to disulfides through treatment with a mild oxidant like iodine (I2).
- A second oxidation pathway involves oxidation of sulfides to sulfoxides and sulfones through treatment with oxidants such as O3 (ozone) and peroxyacids such as m-chloroperoxybenzoic acid (mCPBA). Note that sulfur can exceed an octet of electrons whereas oxygen cannot.
The oxidation of thiols to disulfides has important biological implications. The important amino acid cysteine contains a thiol group and disulfide bonds are responsible for the tertiary structures of proteins. They act like “hooks” that help to hold disparate parts of the peptide chain together.
B. Hydrogen Bonding Isn’t As Significant With Thiols
The electronegativity of sulfur is only 2.6 whereas hydrogen is 2.2. That means there isn’t much of a dipole in the S-H bond, and hydrogen bonding is not significant. Contrast H2O, with a boiling point of 100°C, with H2S and its boiling point of –60°C. Intermolecular forces are not very strong!
C. Reactions With Acids Are Slightly Different
In this series on alcohols and ethers we have seen countless examples of treating an alcohol or ether with H+ and converting it to its conjugate acid, making a better leaving group in the process.
This isn’t as significant for thiols. The S-H bond is significantly weaker than the O-H bond [81 kcal/mol vs. 109 kcal/mol].
Secondly, due to the smaller dipole (electronegativity difference) of the S-H as opposed to O-H, there is less partial negative charge on sulfur and therefore less electrostatic attraction between S and the H of various acids.
A better way of converting sulfur to a good leaving group is by treating it with Lewis acids such as Hg(OAc)2 . We haven’t really covered Hard-Soft Acid Base (HSAB) theory here on MOC (which is an advanced topic) but in order to further understand the differences in reactivity of O and S with various acids, the linked Wikipedia article is a useful primer.
D. There are no “thio” versions of many reactions of alcohols
We’ve seen many interesting reactions that have led to alcohols and epoxides. For example, treatment of alkenes with OsO4 results in vicinal diols. It’s tempting to think that there might be an analogous reaction between alkenes and OsS4 to give vicinal dithiols. There isn’t (and it’s not for lack of trying). Nor is there a sulfur equivalent to the formation of epoxides from alkenes with, say, the sulfur equivalent of mCPBA. So while moving down a column of the periodic table can sometimes provide useful inspiration for new reactions, often – for unclear reasons – it does not.
In the next post (our last on alcohols) we’ll tie all the reactions we’ve learned together into a “reaction map”.
Next Post: Synthesis (6) Reactions of Alcohols
In grad school a visiting speaker gave a talk on making thioaldehydes and thioketones. I missed it, but an emeritus professor who had a hood in our lab was able to attend. He reported back: “What I learned from today’s seminar about the C=S bond…. is that you don’t want to make compounds with C=S bonds”, he said with a laugh. [They’re quite unstable]
[Caveat: This applies to thioaldehydes/thioketones. Molecules like thioamides or thioureas where an atom like N or O are adjacent to the carbon bearing C=S are generally reasonably stable]
Note 2: Relevant video for this post.
- Acidic dissociation constants of thiols
James P. Danehy and K. N. Parameswaran
Journal of Chemical & Engineering Data 1968, 13 (3), 386-389
This contains a list of pKa’s for over 100 thiols. Very useful reference.
- Synthesis of thiols, sulfides, sulfoxides and sulfones
Christopher M. Rayner
Synth. 1995, 2, 409-440
Nice review on sulfur chemistry in organic synthesis.Notable medicinal chemist Derek Lowe has a series of posts titled “Things I won’t work with” on his (excellent) blog. Two of the compounds below make the list because of their vile smells – thioacetone (CH3CSCH3) and selenophenol (PhSeH).
- https://blogs.sciencemag.org/pipeline/archives/2012/05/15/things_i_wont_work_with_selenophenolSulfur atoms on an adjacent carbon can ‘assist’ with reactivity. This is known as ‘Neighboring Group Participation’ or ‘Anchimeric Assistance’. This was first observed by the famed chemist Prof. Saul Winstein (UCLA), who made fundamental contributions to Physical Organic Chemistry.
- Kinetics of Hydrolysis and Displacement Reactions of β,β′-Dichlorodiethyl Sulfide (Mustard Gas) and of β-Chloro-β″-hydroxydiethyl Sulfide (Mustard Chlorohydrin)
Paul D. Bartlett and C. Gardner. Swain
Journal of the American Chemical Society 1949, 71 (4), 1406-1415
- The Hydrolysis of Bis(2-chloroethyl) Sulfide (Sulfur Mustard) in Aqueous Mixtures of Ethanol, Acetone and Dimethyl Sulfoxide
Aust. J. Chem. 1993, 46, 293-300
One of the prime examples of neighboring group participation is the hydrolysis of ‘sulfur mustard’. The sulfur atom allows this molecule to hydrolyze extremely easily (yielding HCl), since it can form a 3-membered episulfonium intermediate.
- Hydrolysis of mustard derivatives in aqueous acetone-water and ethanol-water mixtures
Yu Chu Yang, J. Richard Ward, and Thomas Luteran
The Journal of Organic Chemistry 1986, 51 (14), 2756-2759
- Neighboring group participation by sulfur involving four-membered-ring intermediates (RS-4)
Ernest L. Eliel and David E. Knox
Journal of the American Chemical Society 1985, 107 (10), 2946-2952
Sulfur atoms further out can also act as neighboring groups, geometry permitting.Disulfide bond formation:
- Kinetics and mechanism of the oxidation of n-dodecanethiol and pyridine-substituted ethanethiols by iodine molecule in acetonitrile
David L. De Leeuw, W. Kenneth Musker, and Joyce Takahashi Doi
The Journal of Organic Chemistry 1982, 47 (25), 4860-4864
This goes over the mechanism of the oxidation of thiols with I2, and includes a mechanism and kinetic rate equation.
The oxidation of thiols to disulfides is hugely important in biology, due to the naturally occurring amino acid Cysteine. The importance of Cysteine in biochemistry is due to the fact that the -SH group can form disulfide bonds, which is one of the forces leading to the tertiary structure of peptides and proteins. Synthetic peptides with 2 or more Cys residues can be oxidized to give a disulfide bond, and when 3 or more are present, this is something that needs to be done selectively, as the link explains.Due to their even worse smells, organoselenium and -tellurium chemistry has progressed much slower than related thiol chemistry.
- Theoretical Calculation of pKa’s of Selenols in Aqueous Solution Using an Implicit Solvation Model and Explicit Water Molecules
Bishnu Thapa and H. Bernhard Schlegel
The Journal of Physical Chemistry A 2016, 120 (44), 8916-8922
Theoretical calculations are not the same as experimental determination, but this gives a place to start.
- Phenylseleno neighboring group. Solvolysis of 2-phenylselenoethyl chloride
Samuel P. McManus and David Hinkle Lam
The Journal of Organic Chemistry 1978, 43 (4), 650-651
Selenium can also engage in neighboring group participation.
This publication by Sigma-Aldrich contains a review on organotellurium chemistry.