Imperial College London

Henry Rzepa

The reduction of cinnamaldehyde by lithium aluminium hydride (LAH) was
reported in a classic series of
experiments\[cite\]10.1021/ja01197a060\[/cite\],\[cite\]10.1021/ja01202a082\[/cite\],\[cite\]10.1021/ja01190a082\[/cite\]
dating from 1947-8. The reaction was first introduced into the organic
chemistry laboratories here at Imperial College decades ago, vanished
for a short period, and has recently been reintroduced again.^‡^ The
experiment is really simple in concept; add LAH to cinnamaldehyde and
you get just reduction of the carbonyl group; invert the order of
addition and you additionally get reduction of the double bond. Here I
investigate the mechanism of these reductions using computation
(ωB97XD/6-311+G(d,p)/SCRF=diethyl ether).

[![LAH](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/03/LAH.svg){.aligncenter
.size-full .wp-image-13691 decoding="async"
width="550"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/03/LAH.svg)  
The mechanism can be envisaged as proceeding through a 1,4-hydride
attack (TS14) with a *hidden* intermediate (HI14) on the reaction path,
or instead finding a pathway involving either one or two consecutive
1,2-attacks; TS12-1, TS12-2 *via* an explicit intermediate I12.
Experiment shows that quenching with D~2~O at the end of the reduction
to replace a C-Al with a C-D bond certainly seems to rule out the 1,4
route, since that would not lead to incorporation of deuterium at the
benzylic position. So does the computational model reflect this reality?

|         |                       |                                                                                          |
|---------|-----------------------|------------------------------------------------------------------------------------------|
| Species | Relative ΔG, kcal/mol | [FAIR Data](https://www.force11.org/group/fairgroup/fairprinciples){target="_blank"}-DOI |
| R       | 0.0                   | \[cite\]10.14469/ch/191154\[/cite\]                                                      |
| TS14    | +11.7                 | \[cite\]10.14469/ch/191148\[/cite\]                                                      |
| P14     | -38.8                 | \[cite\]10.14469/ch/191152\[/cite\]                                                      |
| TS12-1  | +8.4                  | \[cite\]10.14469/ch/191149\[/cite\]                                                      |
| I12     | -35.8                 | \[cite\]10.14469/ch/191151\[/cite\]                                                      |
| TS12-2  | +6.5 (42.3)           | \[cite\]10.14469/ch/191156\[/cite\]                                                      |
| P12     | -52.4                 | \[cite\]10.14469/ch/191155\[/cite\]                                                      |

I have chosen a model in which two dimethyl ether molecules solvate the
lithium cation. The reactant itself has an interesting structure, in
which two of the Al-H bonds form bridges to the Li, which ends up being
five-coordinated. Further weak C-H...O=C hydrogen bonding is also
observed. The NCI (non-covalent-interaction) surfaces are well worth
inspecting (inspection notes: the NCI surrounding the Al has artefacts,
since the value of the electron density surrounding the metal is lower
than covalent density for the other elements. Click on the image below
to load the 3D model).

::: {#attachment_13748 .wp-caption .aligncenter style="width: 410px"}
![Click for
3D](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-R-NCI.jpg){.size-full
.wp-image-13748 decoding="async"
aria-describedby="caption-attachment-13748"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2015/04/LAH-R_den.cub.xyz;isosurface  wp-content/uploads/2015/04/LAH-R_den.cub.jvxl;');"
width="400"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-R-NCI.jpg 480w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-R-NCI-300x226.jpg 300w"
sizes="(max-width: 480px) 100vw, 480px"}

Click for 3D
:::

TS14 retains that C-H...O=C hydrogen bond, but the double Al-H-Li bridge
is lost. The 8-ring for the TS allows the hydride transfer to be
approximately linear, and the Bürgi-Dunitz angle of approach of the
hydride to the double bond is 107.4°. Whilst the barrier is acceptably
low, the reaction reaches a cul-de-sac down this path; it has no low
energy escape route.

::: {#attachment_13702 .wp-caption .aligncenter style="width: 410px"}
![TS14](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/03/TS14.jpg){.aligncenter
.size-full .wp-image-13702 decoding="async"
aria-describedby="caption-attachment-13702"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2015/03/LAH-14-985.148076.log;frame 3;spin 3;');"
width="400"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/03/TS14.jpg 677w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/03/TS14-300x202.jpg 300w"
sizes="(max-width: 677px) 100vw, 677px"}

Click for 3D
:::

TS12-1 loses the C-H...O=C hydrogen bond, but being 3.3 kcal/mol lower
in free energy than TS14 fortunately provides a lower energy alternative
to that cul-de-sac! The Bürgi-Dunitz angle is 112.0°.  
![TS12-1](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/03/TS12-1.jpg){.aligncenter
.size-full .wp-image-13703 decoding="async"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2015/03/LAH-12-1-985.1534053.log;frame 79;spin 3;');"
width="400"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/03/TS12-1.jpg 560w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/03/TS12-1-300x249.jpg 300w"
sizes="(max-width: 560px) 100vw, 560px"}  
[![LAH12-1](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH12-1.gif){.aligncenter
.size-full .wp-image-13770 decoding="async"
width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH12-1.gif)

TS12-2 is required to proceed further to the dihydrocinnamyl alcohol
reduction product P12, and now we have to confront the nub of the
problem. Why does this further reduction only proceed when the LAH is in
excess? TS12-2 itself corresponds to an [Al-H
addition](http://www.ch.imperial.ac.uk/rzepa/blog/?p=11995 "The wrong trousers: the anti-Markovnikov addition of borane to 2-methylpropene."){target="_blank"}
across a C=C double
bond.\[cite\]10.6084/m9.figshare.1362146\[/cite\]^†^, with a similar
barrier to TS12-1. The answer to this conundrum is to recognise that I12
forms what is called a *resting state* for the reaction, and that to
proceed further the reaction has to overcome the barrier from I12 to
TS12-2. That barrier is 42.3 kcal/mol, far too high to proceed
thermally. When one encounters an *unreasonable* barrier, one has to
look very carefully at the model one has constructed for the process.  

::: {#attachment_13756 .wp-caption .aligncenter style="width: 410px"}
![Click for
3D](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/ts12-2.jpg){.size-full
.wp-image-13756 decoding="async"
aria-describedby="caption-attachment-13756"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2015/04/TS12-2-985.156404.log;frame 2;spin 3;');"
width="400"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/ts12-2.jpg 540w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/ts12-2-300x189.jpg 300w"
sizes="(max-width: 540px) 100vw, 540px"}

Click for 3D
:::

  
[![LAH12-2a](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH12-2a.gif){.aligncenter
.size-full .wp-image-13799 decoding="async"
width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH12-2a.gif)

Clearly, the model I used here is lacking something. Since the reaction
only proceeds when LAH is in excess, we can formulate the hypothesis
that further LAH must be added to the model, from which a more
reasonable barrier might emerge. If I find out how that can be done, I
will report back here.

------------------------------------------------------------------------

^‡^ LAH as a reagent was originally available in powder form, which
could be quite tricky to handle and could cause fires if not handled
properly. The lab organiser Chris tells me it now comes in
standard-sized
[pellets](http://www.sigmaaldrich.com/catalog/product/aldrich/323403?lang=en&region=GB){target="_blank"}
which are far easier and safer to handle in a laboratory, allowing its
re-introduction.  
^†^**Biographical note.** This footnote is added because I spent three
years as a [Ph.D.
student](http://doi.org/10044/1/20860){target="_blank"} trying to
construct transition state models by measuring kinetic isotope effects.
My failure to do so convincingly meant I decided to spend a further
three years as a Post Doc inverting the concept by learning how to model
transition states using quantum mechanical computation. I first applied
these skills as an independent researcher to locating the transition
state for Cl-H addition (vs Al-H in this post) across a C=C double bond
and computing the associated isotope
effects.\[cite\]10.1039/C39810000939\[/cite\] This article ends with the
assertion that "*SCF-MO calculations may provide a more rational basis
for interpreting kinetic isotopes than the reverse procedure of
attempting to establish a transition state model from the observed
kinetic data.*" It is nice to see that
[posterity](http://www.ch.imperial.ac.uk/rzepa/blog/?p=9105 "The Benzidine rearrangement. Computed kinetic isotope effects."){target="_blank"}
has shown that this assessment was about right.

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


The reduction of cinnamaldehyde by lithium aluminium hydride (LAH) was reported in a classic series of experiments[cite]10.1021/ja01197a060[/cite],[cite]10.1021/ja01202a082[/cite],[cite]10.1021/ja01190a082[/cite] dating from 1947-8. The reaction was first introduced into the organic chemistry laboratories here at Imperial College decades ago, vanished for a short period, and has recently been reintroduced again.
<sup>
 ‡
</sup>
The experiment is

Publicaciones de Rogue Scholar

Mechanism of the Lithal (LAH) reduction of cinnamaldehyde.