Imperial College London

Henry Rzepa

I have [previously
commented](http://www.ch.imperial.ac.uk/rzepa/blog/?p=14016){target="_blank"}
on the Bürgi--Dunitz angle, this being the preferred approach trajectory
of a nucleophile towards the electrophilic carbon of a carbonyl group.
Some special types of nucleophile such as hydrazines (R~2~N-NR~2~) are
supposed to have enhanced
reactivity\[cite\]10.1016/S0040-4020(01)93101-1\[/cite\] due to what
might be described as buttressing of adjacent lone pairs. Here I focus
in on how this might manifest by performing searches of the Cambridge
structural database for intermolecular (non-bonded) interactions between
X-Y nucleophiles (X,Y= N,O,S) and carbonyl compounds OC(NM)~2~.

![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/sq.jpg){decoding="async"
width="400"}

The search query\[cite\]10.14469/hpc/487\[/cite\] is shown above and
involves plotting the distance from the nucleophilic atom (N above) to
the carbon of the carbonyl group. The carbon is defined as having
3-coordination, one of which is O=C and two non-metal attachments. The
torsion is constrained to values of \|70-110\|° to ensure that the
approach of the nucleophile is approximately perpendicular to the plane
of the carbonyl in order to overlap with the π\*-orbital as
electrophile. The pairwise sums of van der Waals radii are NC, 3.25; OC,
3.22 and SC, 3.5Å and the plots show all contacts shorter than
these. The results of the searches are shown below.

![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/nn-c_o.jpg){decoding="async"
width="400"}

![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/oo-c_o.jpg){decoding="async"
width="400"}

![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/05/ss-c_o.jpg){decoding="async"
width="400"}

The general observation is that the red hotspots do tend to come at
trajectory angles of \<100° and many are \<90° such as the X=Y=N or
X=Y=S examples. Given that the original Bürgi--Dunitz hypothesis
(actually based on a small number of molecules synthesized for the
purpose) proposed rather larger angles (105±5°) corresponding to optimum
alignment of the nucleophile with the carbonyl π\*-orbital, we might
speculate whether the use of enhanced nucleophiles is the reason for the
apparent decrease in the angle. And if so, what the underlying reasons
would be.

I also cannot help but observe that the term
[**supernucleophile**]{style="color: #ff0000;"} is quite rare in the
literature; SciFinder gives only 45 hits, but most are about neither
hydrazines nor peroxides. There are also some unusual nucleophile
varieties such as Cob(I)alamin\[cite\]10.1021/jp050802m\[/cite\], of
which there are probably insufficient examples to reflect in the crystal
structure statistics shown above. Given the interest in
[superbases](https://en.wikipedia.org/wiki/Superbase), the relative lack
of examples of unusual supernucleophiles seems surprising.

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

I have previously commented on the Bürgi–Dunitz angle, this being the preferred approach trajectory of a nucleophile towards the electrophilic carbon of a carbonyl group. Some special types of nucleophile such as hydrazines (R

 2

N-NR

 2

) are supposed to have enhanced reactivity[cite]10.1016/S0040-4020(01)93101-1[/cite] due to what might be described as buttressing of adjacent lone pairs.

What is the approach trajectory of enhanced (super?) nucleophiles towards a carbonyl group?

The
[Bürgi--Dunitz](http://en.wikipedia.org/wiki/Bürgi–Dunitz_angle){target="_blank"
rel="noopener"} angle is one of those memes that most students of
organic chemistry remember. It hypothesizes the geometry of attack of
a [nucleophile](http://www.ch.imperial.ac.uk/rzepa/blog/?p=12678) on
a trigonal unsaturated (sp^2^) carbon in a molecule such as ketone,
aldehyde, ester, and amide carbonyl. Its value obviously depends on the
exact system, but is generally taken to be in the range 105-107°. A very
good test of this approach is to search the crystal structure database
(this was how it was originally
established\[cite\]10.1016/S0040-4020(01)90678-7\[/cite\]).

[![search-BD](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/search-BD.jpg){.aligncenter
.size-full .wp-image-14017 decoding="async" width="440"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/search-BD.jpg 748w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/search-BD-300x214.jpg 300w"
sizes="(max-width: 748px) 100vw, 748px"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/BD.qry)The
search is defined as follows

1. R can be either H or C
2. The carbon is constrained to 3-coordinate
3. The carbonyl oxygen is constrained to 1-coordinate
4. QA can be any of N, O, S, Cl, F.
5. QB can be any of H (aldehyde), C (ketone), N (amide), O (ester) or S
 (thioester).
6. The distance QA...C is constrained to any ***intermolecular
 non-bonded contact*** ≤ the sum of the van der Waals radii of the
 two atoms involved and the angle QA...C=O is the Bürgi--Dunitz
 angle.
7. I have also added a torsion constraint to specify that Nu has got to
 be ± 20° from orthogonality to the plane of the carbonyl to allow it
 to attack the π\* orbital.
8. The crystallographic R factor must be \< 0.05, no disorder, no
 crystallographic errors and the temperature is either any or \<
 120K.

With no temperature specified, 6994 hits are obtained as below. So the
most probable angle (red spot) is \~90°.

[![BD](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/BD.jpg){.aligncenter
.size-full .wp-image-14022 decoding="async" width="440"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/BD.jpg 683w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/BD-300x262.jpg 300w"
sizes="(max-width: 683px) 100vw, 683px"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/BD.jpg)

One important change to the search is to decrease the temperature to
120K, since structures will have less vibrational noise. The number of
hits decreases to 1279, but the most probable angle if anything reduces
slightly.

[![BD-120K](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/BD-120K1.jpg){.aligncenter
.size-full .wp-image-14024 decoding="async" width="440"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/BD-120K1.jpg 674w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/BD-120K1-300x232.jpg 300w"
sizes="(max-width: 674px) 100vw, 674px"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/05/BD-120K1.jpg)

So we have something of a mystery; this crystallographic data shows an
angle of approach about 15° less than the oft quoted value. Here are
some thoughts:

1. This search is the average for all types of carbonyl, whereas the
 original suggestion was constrained to four types of nucleophiles
 and simple ketones.
2. This search extends the interacting distance of the nucleophile and
 the carbon out to 3.5Å which is significantly longer than the
 normally considered length of \~2.85Å. The hotspots occur at about
 3.15Å and not 2.85Å.
3. There is obviously considerably more data available in 2015 than in
 1974, and in particular at low temperature.
4. The Bürgi--Dunitz angle is in fact one of two defining the
 trajectory, the other being the [Flippin--Lodge
 angle](http://en.wikipedia.org/wiki/Flippin%E2%80%93Lodge_angle "Flippin–Lodge angle")
 which defines the displacement towards R or QB. The search above
 gives no direct information about this angle, but the torsion is
 related since it is constrained to bisect the C=O to within ± 20°
 and hence bisect the groups R and QB.
5. An angle of ≤ 90° does not match to the normal explanation, which is
 that the nucleophile attacks the π\* orbital, each lobe of which
 \"[leans out](http://www.ch.imperial.ac.uk/rzepa/blog/?p=11331)\"
 from the centre at about 105° rather than leaning in at ≤ 90°.
6. Decreasing the torsion range to  ± 5° at 120K gives 592 hits with a
 hot spot at 95°
7. Also constraining the distance QA...C to be 0.3Å less than the van
 der Waals sum at 120K gives 59 hits with a hot spot at 95° and 2.9Å.

Well, to get to the bottom of this will require reducing the scope of
both QA and QB, to find which if any of discrete values for these two
variables can indeed give an angle of 105-107°. This would make for
quite a good student group project; I expect a group of 8 students could
sort this out quite quickly!

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

#### Acknowledgments

This post has been cross-posted in PDF format at
[Authorea](https://doi.org/10.15200/winn.143149.99424){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"}
:::

The Bürgi–Dunitz angle is one of those memes that most students of organic chemistry remember. It hypothesizes the geometry of attack of a nucleophile on a trigonal unsaturated (sp

 2

) carbon in a molecule such as ketone, aldehyde, ester, and amide carbonyl.

Messaggi di Rogue Scholar

What is the approach trajectory of enhanced (super?) nucleophiles towards a carbonyl group?

The Bürgi–Dunitz angle revisited: a mystery?