Imperial College London

Henry Rzepa

This is a
[follow-up](http://www.ch.imperial.ac.uk/rzepa/blog/?p=10641 "How should one represent the anion of TosMIC?"){target="_blank"}
to comment posted by Ryan, who asked about isocyanide's role (in the
form of the anion of tosyl isocyanide, or TosMIC): "In Van Leusen, it
(the isocyanide) acts as an electrophile". The [Wikipedia
article](http://en.wikipedia.org/w/index.php?title=Van_Leusen_reaction){target="_blank"}
(recently updated by myself) shows nucleophilic attack by an oxy-anion
on the carbon of the C≡N group, with the isocyanide group acting as the
acceptor of these electrons (in other words, the electrophile). In the
form shown below, one negatively charged atom appears to be attacking
another also carrying a negative charge. Surely this breaks the rules
that like charges repel? So we shall investigate to see if this really
happens.

![VL1](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/05/VL1.svg){.aligncenter
.size-full .wp-image-10661 decoding="async" width="420"}

I have extended the basic mechanistic scheme below to investigate other
possibilities (with the aim of probing using the
ωB97XD/6-311G(d,p)/scrf=methanol theory to see how realistic any of
these routes might be). Starting from **1**, the product **6** can now
be formed by three routes from the common intermediate **3** (there may
be other routes of course not considered here). The relative computed
free energies of these various species, and some of the transition
states leading to them are listed in the table
below.![VanLeusen](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2013/05/VanLeusen.svg){.aligncenter
.size-full .wp-image-10665 decoding="async"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2013/05/TosMIC-TS2.log;frame 3;vectors on;vectors 4;vectors scale 5.0; color vectors green; vibration 10;animation mode loop;measure 6 8 4;');"
width="440"}

The path leading to **3** is very low energy which may in part also be
due to my using formaldehyde for expediency rather than a substituted
aldehyde (I have to confess to having taken another short-cut, which is
to miss out any counter-ion to the TosMIC anion). The first step is
defined by **TS1**, which forms a C-C bond, and results in the
intermediate **2**. **TS2** corresponds to O...C bond formation to yield
**3**. Getting to **3** is thus a two-stage process, or a stepwise
cycloaddition. The alternative would have been to regard TosMIC anion as
a 1,3-dipole ([isoelectronic with
e.g.diazomethane](http://www.ch.imperial.ac.uk/rzepa/blog/?p=10641 "How should one represent the anion of TosMIC?"){target="_blank"})
in which these two steps are conflated into a concerted cycloaddition
across the carbonyl group.

**TS2** is the interesting step from the point of view of the question
raised above. It has a very low free-energy barrier from either **1** or
**2**, and therefore appears very facile. The angle of approach by the
oxy-anion to the triple bond (we established it as being triple in the
[previous
post](http://www.ch.imperial.ac.uk/rzepa/blog/?p=10641 "How should one represent the anion of TosMIC?"){target="_blank"})
is 87°. This angle explains why a carbon bearing (a formal) negative
charge easily accepts attack on itself by a nucleophile (*i.e.* acting
as an electrophile). The formal negative charge originates from an
electron lone pair located in an sp-hybrid orbital lying along the axis
of the C≡N bond. But the nucleophilic attack is occurring at 87° to this
axis, putting electrons into the empty π\* orbital of the C≡N bond. So
in effect the two apparent "negative charges" in the mechanistic schemes
above are orthogonal to each-other, which in a simplistic way explains
why the diagram is not actually contradictory. The reaction itself is an
example of [Baldwin's rules in
action](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6921 "Transition state models for Baldwin dig(onal) ring closures."){target="_blank"};
one of these is that a *5-endo-dig* cyclisation is allowed. This angle
of attack and Baldwin's rules may of course be related.

|        |                      |
|--------|----------------------|
| System | Relative free energy |
| 1      | 0.0                  |
| TS1    | 1.2                  |
| 2      | -3.1                 |
| TS2    | 1.7                  |
| 3      | -14.4                |
| 4      | -16.7                |
| TS3    | 5.9                  |
| 5      | 4.0                  |
| TS4    | 17.7                 |
| 6      | -51.1                |
| TS5    | -2.3                 |
| 7      | -3.1                 |
| TS6    | 57.0                 |
| "8"    | -37.4                |
| "9"    | -36.2                |
| 10     | -25.3                |

After **3**, the mechanism can channel several ways. For example, a
proton transfer can precede the departure of **Ts** to give **4** and
thence **5**. The final \[1,2\] shift to form the product **6** has a
relatively high barrier however. More likely is the Ts group
heterolysing off **3** *via* **TS5** to form **7.** All that is now
needed is to shift a proton from **7** to form **6**, and this also can
take several routes. One would involve base/acid catalysed
deprotonation/reprotonation. Alternatively, the hydrogen could migrate
by a series of uncatalysed \[1,5\]sigmatropic hydrogen shifts *via* e.g.
**8**, **9** or **10**. In fact, the calculated geometries of both **8**
and **9** show that the C...O bond is broken, thus forming entirely
different products. Thus the most probable route is indeed a simple
catalysed proton transfer from **7**.

This computational exploration of the mechanism has reinforced the
accepted one, and hopefully cast some light on why an isocyanide can
appear to act as an electrophile.

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


This is a follow-up to comment posted by Ryan, who asked about isocyanide’s role (in the form of the anion of tosyl isocyanide, or TosMIC): “In Van Leusen, it (the isocyanide) acts as an electrophile”. The Wikipedia article (recently updated by myself) shows nucleophilic attack by an oxy-anion on the carbon of the C≡N group, with the isocyanide group acting as the acceptor of these electrons (in other words, the electrophile). In the form shown

Messaggi di Rogue Scholar

Mechanism of the Van Leusen reaction.