Imperial College London

Henry Rzepa

[Previously on this
blog](http://www.ch.imperial.ac.uk/rzepa/blog/?p=13688 "Mechanism of the Lithal (LAH) reduction of cinnamaldehyde."){target="_blank"
rel="noopener"}: modelling the reduction of cinnamaldehyde using one
molecule of lithal shows easy reduction of the carbonyl but a high
barrier at the next stage, the reduction of the double bond. Here is a
quantum energetic exploration of what might happen when a second LAH is
added to the brew (the usual ωB97XD/6-311+G(d,p)/SCRF=diethyl ether).

[![LAH1](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH11.svg){.aligncenter
.size-full .wp-image-13839 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH11.svg)[  
](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH1.svg)  
In a
[comment](http://www.ch.imperial.ac.uk/rzepa/blog/?p=13688&cpage=1#comment-163291){target="_blank"
rel="noopener"} at the end of the first post on this theme, I had noted
some crystal structures containing in effect H~x~Al.Li(OR)~y~ units
(x=3,4; y=0-3), noting the variety of structural motifs. The current
exploration does not even attempt to cover this range of possibilities,
but it is informed by the types of weak interaction that these
structures reveal. I will nevertheless accept that whatever pathway is
revealed here is likely to represent an energetic upper bound and
recognise that lower energy pathways may well exist but are yet to be
explored.

1.  At the **I12** stage, a second AlH~4~^--^.Li(OMe)~2~ is added and
    hydride transfer occurs *antiperiplanar* across the C=C bond
    (**TS34-1**). The computed free energy barrier ΔG~298~^†^ is \~24
    kcal/mol. The magnitude of this barrier corresponds to a relatively
    slow reaction occurring around room temperatures or slightly
    higher.  

    ::: {#attachment_13823 .wp-caption .aligncenter style="width: 410px"}
    ![Click for
    3D](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/lah1.jpg){.size-full
    .wp-image-13823 decoding="async"
    aria-describedby="caption-attachment-13823"
    onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2015/04/TS34-1.log;frame 2;vectors on;vectors 4;vectors scale 8.0;color vectors green;vibration 6;spin 3;');"
    width="400"
    srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/lah1.jpg 834w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/lah1-300x250.jpg 300w"
    sizes="(max-width: 834px) 100vw, 834px"}
    TS. Click for 3D
    :::

      
    [![TS34a](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/TS34a.gif){.aligncenter
    .size-full .wp-image-13897 decoding="async"
    width="400"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/TS34a.gif)  

    ::: {#attachment_13847 .wp-caption .aligncenter style="width: 410px"}
    ![Click for
    3D](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/TS34-NCI.jpg){.size-full
    .wp-image-13847 decoding="async"
    aria-describedby="caption-attachment-13847"
    onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2015/04/TS34_05.cub.xyz;isosurface  wp-content/uploads/2015/04/TS34_05.cub.jvxl;spin 3;');"
    width="400"
    srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/TS34-NCI.jpg 528w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/TS34-NCI-300x236.jpg 300w"
    sizes="(max-width: 528px) 100vw, 528px"}
    NCI Isosurface (green regions are dispersion stabilizing) Click for
    3D
    :::
2.  A transient shallow intermediate **I34-1** is formed in which the
    benzylic anion is stabilised by an adjacent solvated Li centre. The
    energy of this species (Table below) needs some explanation.^‡^ Can
    its free energy really be 1.5 kcal/mol higher than that of the
    preceding transition state? Yes, because its entropy is lower! The
    transition state is located on a total energy surface, which does
    not include thermal and entropic corrections; these are always
    applied AFTER the stationary points are located. If one inspects
    these total energies, **I34-1** emerges as 1.2 kcal/mol lower than
    the preceding transition state. This sort of result serves to remind
    us of the dynamic nature of a potential energy surface, and that
    static energies may on occasion lead to odd results. Its geometry is
    shown below, and this too has an interesting feature. The C-H bond
    just created from the LAH is *antiperiplanar* to the benzylic anion
    (locked *anti* by the Li) and the resulting stereoelectronic effect
    reduces its C-H calculated\[cite\]10.14469/ch/191178\[/cite\]
    stretching wavenumber from the normal value of \~3100 cm^-1^ to 2231
    cm^-1^, a remarkable reduction.  

    ::: {#attachment_13867 .wp-caption .aligncenter style="width: 410px"}
    ![Click for
    3D](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-int1.jpg){.size-full
    .wp-image-13867 decoding="async"
    aria-describedby="caption-attachment-13867"
    onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2015/04/I34-1.log;frame 160;measure 14 47;measure 21 48;measure 44 48;vectors on;vectors 4;vectors scale 8.0;color vectors red;vibration 6;spin 3;');"
    width="400"
    srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-int1.jpg 898w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-int1-300x218.jpg 300w"
    sizes="(max-width: 898px) 100vw, 898px"}
    I34-1. Click for 3D
    :::
3.  The C-O-AlH~3~.Li(OMe)~2~ ligand now needs to rotate to **I34-2** so
    that metal exchange on the benzylic carbon can occur, with Al
    displacing Li at that position. As with **I34-1**, the free energy
    of this species is actually slightly higher than that of **TS34-1**.
    Two AlH~3~ groups now exist at this stage (each of them formed by
    hydride donation as part of the reduction process, see below). A
    hydride transfer metathesis between them (H~2~Al-H-Al~3~ is actually
    a stable bridged species) will generate an AlH~2~ as part of the
    5-ring aluminate ester in **P34** and regenerate a molecule of LAH.
    Transition states for these processes (*i.e.* TS34-2) proved
    difficult to locate;^†^ it may be that the ligand rotation and the
    hydride metathesis are part of the same concerted process but that
    is not proven yet.  

    ::: {#attachment_13871 .wp-caption .aligncenter style="width: 410px"}
    ![Click for
    3D](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-int2.jpg){.size-full
    .wp-image-13871 decoding="async"
    aria-describedby="caption-attachment-13871"
    onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2015/04/I34-2.log;frame 1;measure 39 46;measure 46 41;spin 3;');"
    width="400"
    srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-int2.jpg 919w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-int2-300x245.jpg 300w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/04/LAH-int2-900x736.jpg 900w"
    sizes="(max-width: 919px) 100vw, 919px"}
    I34-2. Click for 3D
    :::
4.  The final product prior to hydrolysis is appropriately exoenergic.
5.  I would also remark that many aspects of this reaction remain
    unexplored. For example, AlH~4~ can deliver up to four hydrides,
    becoming progressively substituted as Al(OR)~n~H~y~ and in the
    process loosing Al-H...Li weak interactions. What influence this has
    on the barriers remains unknown.

|         |                            |                                                                                                         |
|---------|----------------------------|---------------------------------------------------------------------------------------------------------|
| Species | Relative ΔG~298~, kcal/mol | [FAIR Data](https://www.force11.org/group/fairgroup/fairprinciples){target="_blank" rel="noopener"}-DOI |
| I12     | 0.0                        | \[cite\]10.14469/ch/191172\[/cite\]                                                                     |
| TS34-1  | 24.1                       | \[cite\]10.14469/ch/191177\[/cite\]                                                                     |
| I34-1   | 25.5^‡^                    | \[cite\]10.14469/ch/191178\[/cite\]                                                                     |
| I34-2   | 25.0^‡^                    | \[cite\]10.14469/ch/191181\[/cite\]                                                                     |
| P34     | -8.8                       | \[cite\]10.14469/ch/191171\[/cite\]                                                                     |

In summary, the first step in the reduction of cinnamaldehyde to
cinnamyl alcohol requires just one molecule of "LiAlH~4~" as reductant
and has a very low barrier to reaction. To construct a reasonable model
to account for the slower further reduction of the C=C bond requires
adding a further LiAlH~4~, the key feature being the availability of a
lithium centre to stabilise out the forming benzylic carbanion. No doubt
even better models might include the effects of adding *e.g.* a third
molecule of LAH, and a much more extensive exploration of the various
conformational options. But I think the present model might be good
enough to augment the apparently relatively limited mechanistic
speculations found in text books on the topic.

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

^†^You sometimes see this phrase in articles reporting transition state
location. What is means it that I tried a half-dozen what I thought were
reasonable possibilities, and none of them satisfactorily converged.
This semi-random exploration of the potential energy surface revealed a
very flat energy potential, with lots of conformational possibilities.
At this point, you have to decide whether it is worth the time to
continue hunting.

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

#### Acknowledgments

This post has been cross-posted in PDF format at
[Authorea](https://doi.org/10.15200/winn.143118.80740){rel="noopener"
target="_blank"}.

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


Previously on this blog: modelling the reduction of cinnamaldehyde using one molecule of lithal shows easy reduction of the carbonyl but a high barrier at the next stage, the reduction of the double bond.

Postagens de Rogue Scholar

A better model for the mechanism of Lithal (LAH) reduction of cinnamaldehyde?