Imperial College London

Henry Rzepa

The Baeyer-Villiger rearrangement was named after its discoverers, who
in [1899](http://dx.doi.org/10.1002/cber.189903203151 "Einwirkung des Caro'schen Reagens auf Ketone"){target="_blank"} described
the transformation of menthone into the corresponding lactone using
Caro's acid (peroxysulfuric acid). The mechanism is described in all
text books of organic chemistry as involving an alkyl migration. Here I
take a look at the scheme described by Alvarez-Idaboy, Reyes and
Mora-Diez\[cite\]10.1039/b712608e\[/cite\], and which may well not yet
have made it to all the text
books\![![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv1.svg "bv"){.aligncenter
.wp-image-6625 loading="lazy" decoding="async" width="400"
height="355"}](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv1.svg)

The text-book mechanism involves pathway (**a**, R=CF~3~) *via*
species** 1** and **2**. A characteristic feature of many a mechanism of
this type is the need for a step often labelled just PT (proton
transfer). Very often, a proton will find itself attached to the wrong
atom, and before the mechanism can be completed, it must be transferred
to the correct location. Confusingly, there can be many ways of doing
this, differing in the timing of the proton choreography. Deciding that
running order can be perplexing to new students of chemistry. Tutors
often will say that since PTs are very fast, it does not matter when
this step occurs, since in effect all paths will lead to the final
product. But we might imagine that the energies of all the various
pathways can be (in principle) obtained from quantum calculations and
that one will prevail over the others.

Path (**b**) is just one such variation, but with a twist, since it
involves starting from **3** and proceeding *via* a cyclic transition
state in which the migrating alkyl group (shown in red above) moves in
concert with the relocating proton. I have repeated the original
calculations (from 2007) using a somewhat updated procedure, much in the
same way that the transition state for the [aldol
reaction](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6477 "Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular "){target="_blank"}
was. A ωB97XD/6-311G(d,p)/SCRF=dichloromethane
calculation\[cite\]10.14469/ch/13926\[/cite\] of step (**b**) gives the
transition state and associated intrinsic reaction coordinate (IRC)
shown below.

<table style="margin-left: auto; margin-right: auto;" data-border="0">
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<td><div id="attachment_6633" class="wp-caption aligncenter"
style="width: 122px">
<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/BV1.jpg"
title="BV1" class="wp-image-6633" loading="lazy" decoding="async"
aria-describedby="caption-attachment-6633"
onclick="jmolInitialize(&#39;../Jmol/&#39;);jmolSetAppletColor(&#39;white&#39;);jmolApplet([450,450],&#39;load wp-content/uploads/2012/05/BV-7.log;frame 17; zoom 100;connect (atomno=4) (atomno=6) partial;connect (atomno=6) (atomno=12) partial;connect (atomno=1) (atomno=8) partial;connect (atomno=8) (atomno=10) partial;connect (atomno=2) (atomno=12) partial;measure 4 6;measure 6 12;measure 1 8;measure 8 10;measure 2 12;vectors on;vectors 4;vectors scale 5.0; color vectors yellow; vibration 20;animation mode loop;&#39;);"
width="112" height="183" />
<p>Cyclic 7-ring mechanism for the Baeyer-Villiger. Click for 3D.</p>
</div></td>
<td><div id="attachment_6656" class="wp-caption aligncenter"
style="width: 176px">
<a
href="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv-7-forward.gif"><img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv-7-forward.gif"
title="bv-7-forward" class="wp-image-6656" loading="lazy"
decoding="async" aria-describedby="caption-attachment-6656" width="166"
height="190" /></a>
<p>IRC for 7-ring TS, forward direction only.</p>
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<tr class="even">
<td><a
href="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv-7-forward.svg"><img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv-7-forward.svg"
title="bv-7-forward" class="aligncenter wp-image-6657" loading="lazy"
decoding="async" width="227" height="169" /></a></td>
<td><a
href="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv-7-forward-g.svg"><img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv-7-forward-g.svg"
title="bv-7-forward-g" class="aligncenter wp-image-6658" loading="lazy"
decoding="async" width="242" height="185" /></a></td>
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Choreographically, this transition state is quite complex. Five bonds,
all different in some aspect, are changing in asynchronous concert.

1.  Following the transition state\[cite\]10.14469/ch/13929\[/cite\]
    towards the product, between IRC=0 and +4, we see the cleavage of
    the O-O bond occurring in synchrony with the migration of the alkyl
    (methyl) group towards the oxygen (think of it as an S~N~2 reaction
    at oxygen). Notice the antiperiplanar stereoelectronic alignment of
    the migrating (methyl) and the axis of the O-O bond, which strongly
    differentiates which of the two alkyl groups migrates. The
    non-migrating group is essentially orthogonal to the O-O bond.
2.  At IRC = +5 we see a sudden abrupt feature, which corresponds to
    transfer of the proton, and which is complete by IRC = +6. Protons,
    being light, do tend to move quickly when they decide to.
3.  The final noteworthy feature from IRC=+6 to \>20 is the rotation of
    the newly formed methoxy group, starting from orthogonality with the
    carbonyl group (\~IRC +6) to co-planarity (IRC \> 20). The origins
    of this effect are associated with the same
    orthogonal/antiperiplanar stereoelectronic alignments that
    determined which alkyl group migrated earlier.
4.  Notice a minor feature, which is the rotation of the methyl groups
    to set up weaker stereoelectronic interactions.

Path (**c**) is another variation, where an extra molecule of acid (X1,
**4**) helps catalyse the reaction, this time by creating an 11-membered
ring **4** leading to a transition state with potentially two proton
transfers as well as the alkyl
migration.\[cite\]10.14469/ch/13927\[/cite\] By involving an additional
second molecule of acid as catalyst, we now have seven participating
bond changes. Whilst the original path (**b**) six *endo* and *two* exo
electrons move in a cycle which is tantalisingly close to but not quite
pericyclic (?), path (**c**) extends this by four electrons. It might be
tempting to try to apply a selection rule here (such as 4n+2) but I am
not sure it would be justified. 

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<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/BV2.jpg"
title="BV2" class="wp-image-6650" loading="lazy" decoding="async"
aria-describedby="caption-attachment-6650"
onclick="jmolInitialize(&#39;../Jmol/&#39;);jmolSetAppletColor(&#39;white&#39;);jmolApplet([450,450],&#39;load wp-content/uploads/2012/05/BV-11.log;frame 3; zoom 100;connect (atomno=4) (atomno=6) partial;connect (atomno=6) (atomno=12) partial;connect (atomno=1) (atomno=8) partial;connect (atomno=16) (atomno=10) partial;connect (atomno=10) (atomno=16) partial;connect (atomno=8) (atomno=19) partial;connect (atomno=15) (atomno=16) partial;connect (atomno=2) (atomno=12) partial;measure 4 6;measure 6 12;measure 1 8;measure 8 10;measure 2 12;vectors on;vectors 4;vectors scale 5.0; color vectors yellow; vibration 20;animation mode loop;&#39;);"
width="164" height="177" />
<p>Baeyer-Villiger, 11-ring transition state. Click for 3D</p>
</div></td>
<td><a
href="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv2.gif"><img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv2.gif"
title="bv2" class="aligncenter wp-image-6701" loading="lazy"
decoding="async" width="192" height="143" /></a></td>
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title="bv2" class="aligncenter wp-image-6698" loading="lazy"
decoding="async" width="223" height="141" /></a></td>
<td><a
href="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv2g.svg"><img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv2g.svg"
title="bv2g" class="aligncenter wp-image-6699" loading="lazy"
decoding="async" width="209" height="152" /></a></td>
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1.  IRC +3 represents the starting tetrahedral intermediate **4**
    hydrogen bonded to an extra (trifluoroacetic) acid molecule.
2.  The transition state occurs at IRC =0.
3.  By IRC -2, O-O cleavage and methyl migration are essentially
    complete, but no protons have moved.
4.  From IRC -2 to -5, the methoxy group rotates to adopt the planar
    conformation of an ester.
5.  Only after this rotation does the first proton transfer start, at
    IRC -6, and this is then followed in rapid succession by a second at
     -7 to complete the reaction to form ethyl ethanoate and two
    molecules of (trifluoroacetic) acid. This is a reversal of the
    sequence seen with path (**b**). Because no intermediates are
    discernible in the IRC, one must describe this as a *concerted
    rearrangement*, but in fact the bond choreography is far from
    *synchronous*. This is one aspect which conventional  arrow pushing
    does not capture.

To directly compare the energies of paths (b) and (c), we can repeat (b)
with the addition of a more passive acid catalyst, in four new positions
**3**, X2 -- X5. None of these are lower than **4** itself. There is one
more surprise. Species **1** is not actually a minimum, but rearranges
to *e.g.* the cyclic ring shown below. Its free energy is still higher
than that of **3**.

[![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/1-iso.jpg "1-iso"){.aligncenter
.wp-image-6682 loading="lazy" decoding="async" width="129"
height="166"}](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/1-iso.jpg)

I will end with the following speculation. The point of interest to most
students of the Baeyer-Villiger reaction is not the nature of the actual
transition state, but deciding which of the two possible alkyl groups
will migrate (in the example above both are methyls, but if one were
*e.g.* phenyl it would migrate in preference to the methyl). The
transition state teaches us that the group antiperiplanar to the O-O
bond migrates. Can a system be devised where the antiperiplanar
preference takes precedence over the migratory aptitude? For example,
based on the following\[cite\]10.1039/p19940003295\[/cite\] (click to
see 3D structure below in which one R group is clearly pre-disposed to
migrate in preference to the other).

![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/bv11.svg "bv1"){.aligncenter
.wp-image-6692 loading="lazy" decoding="async"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2012/05/PONXIZ.cif; zoom 100;measure 17 10 2 1;measure 23 10 2 1;');"
width="99" height="72"}

::: {.wp_orcid_field}
[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
:::


The Baeyer-Villiger rearrangement was named after its discoverers, who in 1899 described the transformation of menthone into the corresponding lactone using Caro’s acid (peroxysulfuric acid). The mechanism is described in all text books of organic chemistry as involving an alkyl migration.

Messaggi di Rogue Scholar

The mechanism of the Baeyer-Villiger rearrangement.