Hi James,
Interesting. I wonder if this is also dependent on the transport phase that was
used. Do you have any info on that? Was it a typical 10% MeOH or more something
with dichlormethane?
Cheers
Nik
From: James Davidson <j.david...@vernalis.com<mailto:j.david...@vernalis.com>>
Date: Tuesday, October 22, 2013 1:13 PM
To:
"rdkit-discuss@lists.sourceforge.net<mailto:rdkit-discuss@lists.sourceforge.net>"
<rdkit-discuss@lists.sourceforge.net<mailto:rdkit-discuss@lists.sourceforge.net>>
Subject: Re: [Rdkit-discuss] Chemistry 101 question...
Hi JP, Nik, Greg, RDKitters
The question about the lipophilicity (or otherwise) of nitro groups was
interesting to me… I came from a CNS background, where there was, of course, a
stricter requirement for molecules to be suitably lipophilic to cross the
blood-brain barrier. My recollection was that the observed lipophilicity of
nitro groups was dependent on their local environments (ie electron rich / +m
gave more polar character, and electron poor / -m gave more polar character)…
But rather than rely on my hazy recollections, I decided to have a quick look
back at some historical reverse-phase analytical LC data.
What I did was took all retention times (in mins) under one well-used gradient
method, and generated the matched-molecular pairs using George’s KNIME node. I
was then only interested in *[H] >> [*][N+](=O)[O-] transformations, so
filtered-down to just those changes involving 5 atoms in the transformation
(because this was quicker than chemically searching!). I then grouped across
the examples of transformations to give some average changes in retention time,
plus n, range, sd:
Transformation
Mean RT change (min)
RT range (min)
SD
n
*[H]>>[*]CCC
2.5
3.3
0.999
28
*[H]>>[*]C(C)C
2.19
5.47
1.09
37
*[H]>>[*]CCCl
1.91
1.5
1.06
2
*[H]>>[*]C(F)F
1.22
1.36
0.748
3
*[H]>>[*]C1CC1
1.18
1.04
0.436
4
*[H]>>[*]N(C)C
1.08
1.21
0.472
6
*[H]>>[*]CSC
0.67
0
0
1
*[H]>>[*]OCC
0.479
4.67
1.17
15
*[H]>>[*][N+](=O)[O-]
0.169
2.82
0.645
35
*[H]>>[*]NCC
0.0625
0.045
0.0318
2
*[H]>>[*]CCO
0.06
0.04
0.0283
2
*[H]>>[*]COC
-0.001
2.46
0.62
14
*[H]>>[*]CC=C
-0.357
0
0
1
*[H]>>[*]C(C)=O
-0.397
1.21
0.696
3
*[H]>>[*]C(=O)O
-0.848
4.3
2.17
3
*[H]>>[*]CC#N
-1.3
2.35
1.66
2
*[H]>>[*]C(N)=O
-2.72
0
0
1
*[H]>>[*]CCN
-2.77
0
0
1
So on average over the 35 examples of H --> NO2 the change made the molecules
slightly more lipophilic (or, at least, they were retained slightly longer on a
C18 column).
I expect there is much more data-digging that could be done – particularly with
larger data sets, and (maybe) with proper logP / logD measurements; but for now
I am going to stick to thinking NO2 groups can be lipophilic additions(!)
Cheers
James
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