Thiols And Thioethers

Thiols And Thioethers
Here’s a summary of today’s post on thiols:
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
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.
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?
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 78. [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.
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).
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
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
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.
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