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.

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

Singleton and co-workers have produced some wonderful work showing how
dynamic effects and not just transition states can control the outcome
of reactions. Steve Bachrach's blog contains many examples, including
this [recent one.](http://comporgchem.com/blog/?p=2290){target="_blank"}

![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/07/singleton.svg "singleton"){.aligncenter
.wp-image-7101 loading="lazy" decoding="async" width="338" height="116"}

This shows that tolyl thiolate (X=Na) reacts with the dichlorobutenone
to give two substitution products in a 81:19 ratio. [Singleton and Bogle
argue](http://dx.doi.org/10.1021/ol300817a){target="_blank"}\[cite\]10.1021/ol300817a\[/cite\] that
this arises from a ***single transition state***, and that the two
products arise from a statistical distribution of dynamic trajectories
bifurcating out of a transition state favouring **2** over **3**. Steve
puts it very elegantly "*I think most organic chemists hold dear to
their hearts the notion that selectivity is due to crossing over
different transition states*". When I read this, Occam's razor came to
mind: could a simpler (in this case *a *more conventional) answer in
fact be better? 

[My
thoughts](http://comporgchem.com/blog/?p=2290#comments){target="_blank"}
in fact followed a point I have been making here recently, the principle
that [modelling a
complete](http://www.ch.imperial.ac.uk/rzepa/blog/?p=4952){target="_blank"}
system is probably better than a partial one. Now, if you look at Figure
1 of the Singleton/Bogle article, captioned "*Qualitative energy surface
for the reaction of **1** with sodium p-tolyl thiolate*" I was struck by
something missing; the sodium (X=Na), and possibly also explicit solvent
(ethanol). I wanted to see if these missing components may influence the
mechanism.

![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/07/singleton1.svg "singleton1"){.aligncenter
.wp-image-7102 loading="lazy" decoding="async" width="409" height="234"}

The red arrows follow the proposed mechanism (a), whereas the blue
arrows represent a more conventional 1,4-nucleophilic *addition* to form
an intermediate enol anion, this then *eliminating* to the final
product. Singleton & co. explored the potential energy surface using the
following computational model: **B3LYP/6-31+G(d,p)/PCM(ethanol)** for
the anionic system (defined by setting an overall charge of -1 during
the calculation), finding the potential energy surface corresponded to
path (a). They then went on to explore the dynamics of the system
emerging out of this single TS, showing that in fact both products would
be formed in more or less exactly the ratio observed. 

I thought two things could be considered missing from this model; X^+^
(the counterion) and explicit solvent (continuum solvent was invoked
using the PCM model). On the latter point, I have thought for a little
while that there are two types of solvent; those which act *via* their
dielectric field, and those that act *via* hydrogen bonds. Ethanol does
both, and so in this case (I argue) it should be explicitly included
(actually, in the first instance it can be approximated using water
instead of ethanol). The missing counter-ion is a greater challenge. In
what follows I am going to approximate it too, using H^+^ (Na^+^ itself
I reserve for a future post). The objective is to find out what (if
anything) changes when this more complete model is built. It is shown
below as the [first transition
state](http://hdl.handle.net/10042/20231){target="_blank"}
encountered. Its features include:

::: {#attachment_7103 .wp-caption .aligncenter style="width: 292px"}
![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/07/singleton1.jpg "singleton1"){.wp-image-7103
loading="lazy" decoding="async"
aria-describedby="caption-attachment-7103"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2012/07/singleton1-1972.898697.log;frame 3; zoom 100;connect (atomno=7) (atomno=9) partial;connect (atomno=29) (atomno=12) partial;connect (atomno=30) (atomno=31) partial;connect (atomno=7) (atomno=27) partial;measure 7 9;vectors on;vectors 4;vectors scale 5.0; color vectors blue; vibration 20;animation mode loop;');"
width="282" height="227"}

First transition state TS1. Click for 3D
:::

1.  Two explicit solvent (water) molecules.
2.  A H^+^ (I will discuss Na^+^ in another post), attached to one of
    the water molecules as a hydronium ion.
3.  The hydronium ion bridges to the carbonyl group (this is the final
    optimised position; the second water molecule serves only to H-bond
    to the hydronium ion). 
4.  This overall system is neutral, charge=0 (I like to say it might be
    found in a bottle or flask; pure anions of course cannot be
    bottled). 
5.  The model used was
    [B3LYP/6-31+G(d,p)/CPCM(ethanol)](http://hdl.handle.net/10042/20231){target="_blank"};
    I find the CPCM method to be better for calculating intrinsic
    reaction coordinates (IRC).
6.  Using this transition state to initiate an IRC shows that the
    presence of this solvent bridge allows X (=H^+^) to smoothly
    transfer from sulfur to oxygen as part of a concerted process. This
    avoids excessive build up of charge separation.  
    ![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/07/Singleton-TS11.gif "Singleton-TS1"){.aligncenter
    .size-full .wp-image-7155 loading="lazy" decoding="async"
    width="365" height="256"}
7.  This now forms an
    [intermediate](http://hdl.handle.net/10042/20233){target="_blank"}
    (we are clearly following path (**b**) and not path (**a**) now).
    This is because the enolate anion is stabilised by protonation and a
    hydrogen bond from the proton to the solvent water, and so this
    becomes an explicit intermediate in the potential energy surface.  

    ::: {#attachment_7111 .wp-caption .aligncenter style="width: 290px"}
    ![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/07/singleton2.jpg "singleton2"){.wp-image-7111
    loading="lazy" decoding="async"
    aria-describedby="caption-attachment-7111"
    onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2012/07/singleton-int.mol;connect (atomno=9) (atomno=14) partial;measure 7 9;measure 9 14;measure 9 13;');"
    width="280" height="150"}
    Intermediate in reaction. Click for 3D
    :::

This intermediate now collapses along path (**b**) to the final product,
*via* the [transition
state](http://hdl.handle.net/10042/20232){target="_blank"} shown
below. Again, an
[IRC](http://hdl.handle.net/10042/20236){target="_blank"} shows a
solvent bridge allows X to be concertedly transferred, this time from
the oxygen to form [hydronium
chloride](http://www.ch.imperial.ac.uk/rzepa/blog/?p=1749){target="_blank"} and **2**
(I have not yet found the equivalent pathway to **3**, but given the
hydrogen bonds involved it is bound to be different).

::: {#attachment_7117 .wp-caption .aligncenter style="width: 263px"}
![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/07/singleton3.jpg "singleton3"){.wp-image-7117
loading="lazy" decoding="async"
aria-describedby="caption-attachment-7117"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2012/07/singleton2-1972.923626.log;frame 3; zoom 100;connect (atomno=31) (atomno=14) partial;connect (atomno=9) (atomno=14) partial;connect (atomno=29) (atomno=28) partial;connect (atomno=27) (atomno=14) partial;measure 14 9;vectors on;vectors 4;vectors scale 5.0; color vectors blue; vibration 20;animation mode loop;');"
width="253" height="211"}

Second transition state TS2. Click for 3D[ ]{.Apple-style-span
style="font-size: 13px; line-height: 19px;"}
:::

![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/07/Singleton-TS21.gif "Singleton-TS2"){.aligncenter
.wp-image-7147 loading="lazy" decoding="async" width="295" height="196"}

ΔG^†^ (kcal/mol) along this sequence is **1** (0.0), TS1 (28.2), Int
(8.0), TS2 (12.6); the intermediate existing only in a shallow well of
4.6 kcal/mol. The activation barrier is on the high side (the reaction
occurs easily at room temperature), and it might be expected that (in
part) this might be due to using X=H^+^ rather than X=Na^+^ for the
model. Watch this space!

What might we conclude from this? That the presence of additional
molecules (H~3~O^+^ and H~2~O) can result in structures which can depend
on other features of the molecule, in this case the carbonyl group, one
that plays little role in mechanism (a). In path (b), the carbonyl group
is far from passive, receiving and then releasing X during the course of
the reaction. This must mean that the transition state for forming
product **2** may indeed be a separate one from the transition state for
forming product **3**, since the relationship of these two to the
carbonyl is different. To re-quote Steve again "*I think most organic
chemists hold dear to their hearts the notion that selectivity is due to
crossing over different transition states".*

Perhaps the explanation might indeed be due to different transition
states rather than different dynamics? Clearly, more research needs to
be done; I for one do not regard the case as closed on this example just
yet.

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


Singleton and co-workers have produced some wonderful work showing how dynamic effects and not just transition states can control the outcome of reactions. Steve Bachrach’s blog contains many examples, including this recent one. This shows that tolyl thiolate (X=Na) reacts with the dichlorobutenone to give two substitution products in a 81:19 ratio.

Messaggi di Rogue Scholar

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

Dynamic effects in nucleophilic substitution at trigonal carbon.