Application Note: Swern Oxidation, Cryogenic Applications in Flow

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Swern oxidation is well known for the oxidation of alcohols to their corresponding carbonyls and it
demonstrates good functional group selectivity. However, their regular application has been limited so far due
to their low reaction temperature requirement, which is inevitable for maintaining a stable reactive
intermediate. In batch, the ’activated’ dimethyl sulphoxide (DMSO) decomposition has been reported to occur
above -60°C.

In this application note we are about to demonstrate a classical Swern oxidation, conducted in ThalesNano’s
novel IceCube™ Flow Reactor, as an example of performing high energy reactions safely and selectively.

Mandelic acid was discovered in 1831 by the German pharmacist Ferdinand Ludwig Winckler
(1801–1868) while heating amygdalin, an extract of bitter almonds, with diluted hydrochloric
acid.[3] The name is derived from the German "Mandel" for "almond". Derivatives of mandelic acid
are formed as a result of metabolism of adrenaline and noradrenaline by monoamine
oxidase and catechol-O-methyl transferase.
Mandelic acid is usually prepared by the acid-catalysed hydrolysis of mandelonitrile,[4] which is
the cyanohydrin of benzaldehyde. Mandelonitrile can also be prepared by
reacting benzaldehyde with sodium bisulfite to give the corresponding adduct,
forming mandelonitrile with sodium cyanide, which is hydrolyzed:[5]
 Alternatively, it can be prepared by base hydrolysis of phenylchloroacetic acid and
dibromacetophenone.[6] It also arises by heating phenylglyoxal with alkalis.[7][8]
The biotechnological production of 4-hydroxy-mandelic acid and mandelic acid on the basis
of glucose was demonstrated with a genetically modified yeast Saccharomyces cerevisiae, in
which the hydroxymandelate synthase naturally occurring in the bacterium Amycolatopsis was
incorporated into a wild-type strain of yeast, partially altered by the exchange of a gene
sequence and expressed.[9]
It also arises from the biodegradation of styrene, as detected in urine.[10]

Uses[edit]
Mandelic acid has a long history of use in the medical community as an antibacterial, particularly
in the treatment of urinary tract infections.[11] It has also been used as an oral antibiotic, and as a
component of chemical face peels analogous to other alpha hydroxy acids.[12]
The drugs cyclandelate and homatropine are esters of mandelic acid.

Deciding SN1/SN2/E1/E2 (1) – The

Substrate
NOVEMBER 21, 2012 BY JAMES ASHENHURST 39 COMMENTS

Having gone through the SN1, the SN2, the E1, and the E2 reactions in turn,
we can now say the following:

 Both substitution reactions and elimination reactions occur with alkyl

halides (and related species)
 A wide variety of nucleophiles/bases can be used to perform substitution
and elimination reactions
 A wide variety of solvents can be used in substitution and elimination
reactions
  We also have to gauge the importance of factors such as the leaving
group and temperature.

This is a lot of different factors to think about. Let’s look at some examples of
situations you might encounter:

This is often one of the most difficult parts of organic chemistry for new
students: how to weigh multiple (and often contradictory) factors? How do we
know which factor is most important? Do we pay attention to the base,
substrate, temperature, solvent? How do we go about sorting through a
problem like this? As I’ve written before, deciding SN1/SN2/E1/E2 is not
completely unlike how a professional bettor might evaluate which sports team
is going to win on a given night (does good defence beat good offence? how
important is coaching? how important is their recent performance? ) .

In this post and the next few, we’ll walk through one way of thinking about how
to evaluate whether a reaction will proceed through SN1/SN2/E1/E2. It’s not
100% foolproof*, but it’s a decent enough framework for our purposes. Think
of it as a set of 80/20 guidelines. I call it this:

The Quick N’ Dirty Guide To Determining SN1/SN2/E1/E2, Part 1

It starts by asking questions. In order of importance, I think they are:

 1. The substrate
2. The nucleophile/base
3. The solvent
4. The temperature

It’s also an approach where I tend to (at least in the beginning) ruling things
out rather than ruling things “in”. In other words, seek to decide what options
are not possible, rather than decide which are possible. It’s a subtle
distinction, but a valuable one. Once you’ve crossed certain reactions off the
list, you can then start asking yourself which reactions would be most
consistent with the reaction conditions.

Remember: this is the “Quick N’ Dirty” guide! There will be some

exceptions! (more on those at the bottom)

Before getting specific with each of those 4 questions, let’s start with the most
important question you can ask in any situation like the ones above.

The most important step in evaluating any reaction is first to ask yourself
“what type of functional group(s) are present in this molecule? This is
because the type of functional group will dictate the type of reaction(s)
that can occur. Note that in the questions above, all of the starting materials
are alkyl halides or alcohols. Substitution/elimination reactions are possible
for these substrates; many other reaction types (addition, for example) are
not.

Question 1: The Substrate

Given that we’re looking at alkyl halides/alcohols, it’s a reasonable

expectation that we should evaluate SN1/SN2/E1/E2. The next step is to
identify the type of alkyl halide we are dealing with.
Look at the carbon that contains the best leaving group. Typically this is
Cl, Br, I or some other group that can act as a good leaving group.
Ask yourself: is this carbon primary, secondary, or tertiary?

Given what we know about SN1, SN2, E1, and E2 reactions, we can say the
following:

 The “big barrier” to the SN2 reaction is steric hindrance. The rate of
SN2 reactions goes primary > secondary > tertiary
  The “big barrier” to the SN1 and E1 reactions is carbocation stability.
The rate of SN1 and E1 reactions proceeds in the order tertiary >
secondary > primary.
 The E2 reaction has no “big barrier”, per se (although later we will have
to worry about the stereochemistry)

So how can we apply what we know about each of these reactions to simplify
our decision?

Quick N’ Dirty Rule #1: If the substrate is primary, we can rule out SN1 and
E1, because primary carbocations are unstable* (see below for
exceptions). You cannot definitively rule out E2 yet, although I will spill the
beans and say that it’s almost certainly going to be SN2 unless you are using a
very sterically hindered (“bulky”) base such as tert-butoxide ion
(e.g. potassium t-butoxide KOtBu).

Quick N’ Dirty Rule #2: If the substrate is tertiary, we can rule out SN2,
because tertiary carbons are very sterically hindered.

If the substrate is secondary, we can’t rule out anything (yet).

As you can see, based on the information we’ve evaluated so far, we can’t
make a definitive decision on SN1/SN2/E1/E2. We’ll have to look at some
other factors before we can make a final decision. Next, we’ll evaluate the role
of the nucleophile/base.

Next Post: The Role of The Nucleophile

—————-END OF QUICK N’ DIRTY GUIDE, PART 1 ————————–

NOTES: One final word of warning on the substrate: SN1/SN2/E1/E2

reactions tend not to occur on alkenyl or alkynyl halides. So if you see one
of the substrates below, it is highly likely that no reaction will occur.

Why are alkenyl and alkynyl halides so bad? Well, the SN1, SN2, and E1
mechanisms all involve considerable build-up of positive charge on the carbon
bearing the leaving group, and the stability of sp2 and sp hybridized
carbocations is much lower than that for sp3 hybridized carbocations [for the
same reason that sp and sp2 anions are more stable than sp3 carbanions!].

E2 reactions are also more difficult due to the stronger C-H bonds of alkenes.
[We’ll see later that there is one example of an E2 that can occur on alkenyl
halides, but the point remains that they are very rare!]

—————— EXCEPTIONS ————–

* One question that comes up a lot is this: are there exceptions? Keeping in
mind the two themes of “steric hindrance” and “carbocation stability”, there are
edge cases where we can have a particularly sterically hindered primary alkyl
halide, or a particularly stable primary carbocation.
For instance, the alkyl halide below (“neopentyl bromide”) is indeed primary,
but is so crowded on the carbon adjacent to the primary alkyl halide that it is
essentially inert in SN2 reactions. On the SN1/E1 side, the allyl halide below,
while primary, can undergo SN1/E1 reactions because the resulting
carbocation is stabilized through resonance. As long as you keep in mind the
“big barriers” for each reaction, you should be fine.