Thiols And Thioethers

by James

in Alcohols, Organic Chemistry 1

Here’s a summary of today’s post on thiols:

thiol summary

Thiols and Thioethers

One of the most powerful insights from learning the periodic table is the fact elements in the same period (column) have similar chemical properties.

For instance

  • 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.

1. First Things First: Thiols Smell Bad

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.

1-thiol smells

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).

2. Thiols Are More Acidic Than Alcohols

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?

1-acidity

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“].

3. Sulfur: Less Basic, More Nucleophilic

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.

3-nuc-bas

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 ).

4. Common Reactions of Thiolates: SN2 Reactions

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).

4-williamson

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!

5-intramolec

 

5. Key Differences Between Alcohols And Thiols

A. Oxidation

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.

7-oxidation

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.

8-disulfide

 

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


[Note]

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.

Related Posts:

  • No Related Posts

{ 5 comments… read them below or add one }

mamid

Check the text for “vicuna (sic) dithiols”.

Good post, by the way.

Reply

George Dionne

Thanks for the amazing post! The comparison between the two is really clear and detailed, and the difference between thiols and alcohols too.

Reply

John Spevacek

Interesting. I never thought about the lack of analogs. A -CSSH group would be pretty neat.

Reply

Rich

According to Wikipedia, methylselenol has pKa=5.2, compare to methylthiol pKa=8.3 in the same article. Conventionally methylthiol is reported pKa~10.2, so I suspect the first two values may be measured in a solvent other than water. I hope this helps at least a little bit to quantify the relative acidity of organoselenols.

Reply

Era

Thanks for the tutorial!

Reply

Leave a Comment