Evaluating the Viability of Successive Ring-Expansions Based on Amino Acid and Hydroxyacid Side-Chain Insertion

Article abstract of DOI:10.1002/chem.202002164

The outcome of ring-expansion reactions based on amino/hydroxyacid side-chain insertion is strongly dependent on ring size. This manuscript, which builds upon our previous work on Successive Ring Expansion (SuRE) methods, details efforts to better define the scope and limitations of these reactions on lactam and β-ketoester ring systems with respect to ring size and additional functionality. The synthetic results provide clear guidelines as to which substrate classes are more likely to be successful and are supported by computational results, using a density functional theory (DFT) approach. Calculating the relative Gibbs free energies of the three isomeric species that are formed reversibly during ring expansion enables the viability of new synthetic reactions to be correctly predicted in most cases. The new synthetic and computational results are expected to support the design of new lactam- and β-ketoester-based ring-expansion reactions.

Full text of DOI:10.1002/chem.202002164

Accepted Article
Accepted Article
Title: Evaluating the viability of successive ring expansion reactions
based on amino acid and hydroxyacid side chain insertion
Authors: Aggie Lawer, Ryan G. Epton, Thomas C. Stephens, Kleopas
Y. Palate, Mahendar Lodi, Emilie Marotte, Katie J. Lamb,
Jade K. Sangha, Jason M. Lynam, and William Paul Unsworth
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To be cited as: Chem. Eur. J. 10.1002/chem.202002164
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Chemistry - A European Journal
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Evaluating the viability of successive ring expansion reactions
based on amino acid and hydroxyacid side chain insertion
[a]
[a]
[a]
[a]
[a]
Aggie Lawer, Ryan G. Epton, Thomas C. Stephens, Kleopas Y. Palate, Mahendar Lodi, Emilie
[b]
[a]
[a]
[a]
[a]
Marotte, Katie J. Lamb, Jade K. Sangha, Jason M. Lynam* and William P. Unsworth*
[
a]
Mr Ryan G. Epton, Dr Thomas C. Stephens, Mr Kleopas Y. Palate, Dr Mahendar Lodi, Dr Katie J. Lamb, Miss Jade K. Sangha, Dr Jason M. Lynam, Dr
William P. Unsworth
Department of Chemistry
University of York
York, YO10 5DD (UK)
E-mail: jason.lynam@york.ac.uk; william.unsworth@york.ac.uk
Miss Emilie Marotte
[b]
ENSICAEN
6
Boulevard Maréchal Juin,
CS 45053 14050, CAEN,
cedex 04 (France)
Supporting information for this article is given via a link at the end of the document.
Abstract: The outcome of ring expansion reactions based on
amino/hydroxyacid side chain insertion is strongly dependent on ring
size. This manuscript, which builds upon our previous work on
Successive Ring Expansion (SuRE) methods, details efforts to better
define the scope and limitations of these reactions on lactam and β-
ketoester ring systems with respect to ring size and additional
functionality. The synthetic results provide clear guidelines as to which
substrate classes are more likely to be successful and are supported
by computational results, using a Density Functional Theory (DFT)
approach. Calculating the relative Gibbs free energies of the three
isomeric species that are formed reversibly during ring expansion
enables the viability of new synthetic reactions to be correctly
predicted in most cases. The new synthetic and computational results
are expected to support the design of new lactam- and β-ketoester-
based ring expansion reactions.
These methods, which we have termed ‘Successive Ring
[5]
Expansion’ (SuRE) reactions, enable the controlled, iterative
insertion of amino acid or hydroxyacid-derived linear sequences
into cyclic β-ketoesters (4 → 6, Scheme 1b)[5a,b] or lactams (7 →
9, Scheme 1c).[5c,d]
Introduction
Rearrangement reactions that allow ring-enlarged products to be
prepared from smaller cyclic systems have much utility in
synthetic chemistry.[1,2] Ring expansion reactions are particularly
useful for the synthesis of medium sized rings (8–11-membered)
and macrocycles (12+ membered), as alternatives to direct end-
to-end cyclisation reactions.[3] End-to-end cyclisation reactions
can be difficult and unpredictable processes due to competing
intermolecular coupling and other side reactions, and this often
necessitates the use of impractical high-dilution (or pseudo high-
dilution) conditions.[4] In contrast, high dilution can often be
avoided completely in well-designed ring expansion reaction
systems.[1,2,5]
Scheme 1. Side chain insertion ring expansion reactions and Successive Ring
Expansion (SuRE).
Side-chain insertion ring expansion reactions (Scheme 1a)
are a useful sub-class of ring expansion, as the requisite
precursors are generally straightforward to prepare. Various
methods in which the ring expansion is accompanied by
concomitant C–O, C–N and C–C bond formation are known, and
this topic has been recently reviewed.[1a] Amongst this class of
reaction, our group has developed a series side-chain insertion
ring expansion processes that can be performed iteratively.
In our experience, the most important factor in determining the
outcome of new ring expansion reactions of the types
summarised in Scheme 1b and 1c is ring size. This is well
demonstrated by the outcomes of our published lactone-forming
ring expansions of imides of the form 10 (Scheme 2).[5d] Thus, for
both α- and β-hydroxyacid derived linear fragments (3- and 4-
1
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atom ring expansions respectively), there is a clear point at which
ring expansion ‘switches on’; the reactions work for starting
materials with rings that are 8-membered or more for 3-atom
expansions (m = 1) and rings that are 6-membered or more for 4-
atom expansions (m = 2). The analogous reactions fail for smaller
ring variants. We have previously postulated that these reactions
which model solvation and dispersion interactions. Thus, we
believe that this widely available DFT/B3LYP/6-31G* approach
will be useful to help assess the viability of new ring expansion
reactions before committing to synthetic efforts.
are under thermodynamic control, and hence that the reaction Results and Discussion
outcomes depend on the relative Gibbs free energies of the three
isomeric forms that the substrate must pass through for ring
expansion to occur. This idea is supported by calculations
performed at the DFT/B3LYP/6-31G* level of theory;[5d, 6-8] thus, 5-
membered ring-open form imide 12RO (RO = ring-opened) was
calculated to be significantly lower in Gibbs free energy than its
isomeric ring-closed (12RC, RC = ring-closed) and ring expanded
forms (12RE, RE = ring expanded), and this was replicated in the
synthetic results, with imide 12RO being isolated in 99% yield
following hydrogenolysis of the parent benzyl protected imide (10,
where n = 2, m = 1). Conversely, in the case of the analogous 8-
membered starting material (10, where n = 5, m = 1), the ring
expanded form 13RE was calculated to be the most stable isomer,
and upon testing the reaction, 13RE was isolated in 89% yield,
meaning that the calculations again were in line with the synthetic
results.
We started by examining the ring expansion of simple lactams
with sarcosine derivative 15. We had already shown that this acid
chloride is compatible with our standard lactam ring expansion
method (14 → 16, Scheme 3a), but prior to this work, 13-
membered lactam 14 was the smallest aliphatic lactam on which
we have reported a successful ring expansion with any linear α-
amino acid chloride.
Scheme 2. Ring-size dependency on reaction outcome on the ring expansion
of imides into aza-lactones. ΔG°rel values are given in kcal/mol.
Scheme 3. Ring-size dependency on reaction outcome on the ring expansion
of imides into with N-methyl sarcosine derivatives. ΔG°rel values are given in
kcal/mol with thermal corrections at 298 K.
These calculations, which drew inspiration from
a similar
[2d]
approach used by Yudin and co-workers, were done primarily
to validate our ideas about the reactions being under
thermodynamic control. In this work, we have explored the validity
of using calculations of this type predictively. As we continue to
develop this research programme, having a reliable predictive tool
to inform the likelihood of new SuRE variants working before
committing to labour-intensive synthetic efforts will be of value.
The utility of this approach is demonstrated herein; in total, 52 new
ring expansion reactions have been attempted, with 48
successfully furnishing the desired ring expanded product. Our
DFT/B3LYP/6-31G* method correctly predicted the reaction
outcome in almost all cases, and compared favorably when
benchmarked against other alternative methods, including those
Prior to doing the synthetic chemistry, we ran DFT calculations
based on the method used in our earlier study. To summarize this
method, each of the three components of the equilibria deriving
from 5–8-membered ring imide precursors 17RO–20RO were
[6–
optimised at the DFT/B3LYP/6-31G* level of theory in vacuum.
8
]
Conformational searches of the optimised structures were
performed at the Molecular Mechanics Force Field level. All the
generated structures were retained, and their energies were
calculated using DFT/B3LYP/6-31G*. The lowest energy
geometry in each case was selected, fully optimised and
determined to be minima by the absence of negative vibrational
modes, in vacuum using DFT/B3LYP/6-31G*. In each case, the
relative free energies of the imide (17RO–20RO), ring-closed (17RC
–
2
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20RC), and ring expanded (17RE–20RE) isomers were calculated,
with ΔG°rel values quoted in kcal/mol (Scheme 3b). More
information about the choice of this method and method effects
are included later in the manuscript;[7] until then, the discussion
will focus on the synthetic aspects and DFT/B3LYP/6-31G*
calculations.
In the 5–7-membered series, the imide isomers 17RO–19RO
were calculated to be the most stable, suggesting that ring
expansion is unlikely to proceed in these examples. This
prediction was verified by synthetic results; thus, none of the ring
expanded products 17RO–19RO were obtained when attempts
were made to prepare them using the standard conditions, with
no tractable products isolated from these reactions (17RO–19RO,
Scheme 3c). Conversely, the ring-expanded isomer 20RE was
calculated to be the lowest in free energy in the 8-membered ring
series, and this again was borne out in the synthetic results, with
20RE isolated in 82% yield. Thus, the use of an 8-membered ring
starting material (or larger) appears to be the ‘switch on’ point for
this series, as it was for the analogous lactone systems in Scheme
2
.
This is supported by the high yielding (66–94%) ring
expansions of 9–12-membered lactam systems to form products
2
1
RE–24RE under the standard conditions.
Medicinal interest in medium-sized rings and macrocycles
has increased significantly in the last decade,[9] and the reaction
variant described in Scheme 3 appears to be well suited for use
in the preparation of peptoid-containing macrocycles,[10] as long
as the starting lactam is an 8-membered ring or larger. Thus, to
better demonstrate its potential utility, we went on to investigate
the range of N-substituents that can be tolerated on the linear unit
2
6, with these results summarised in Scheme 4. In total, 24 new
ring expansion reactions of this type have been performed, to
make 27a–y (27k was described previously)[5c] using various
functionalised amino acid-derived linear fragments (26). Most of
the reactions proceeded in high yield (the yield quoted is for the
full N-acylation/protecting group cleavage/rearrangement
sequence) under the standard reaction conditions, significantly
expanding the range and diversity of amino acid derivatives that
have been demonstrated in the SuRE method to date.
Scheme 4. Scope of lactam ring expansion reactions with N-functionalised
amino acids
All the new SuRE reactions presented in Scheme 4 worked
at least to some degree), although there were a few outliers that
were lower yielding (e.g. furan-derivative 27v). In these cases, we
believe that the lower yield is not caused by an inherent difference
in the thermodynamics of the ring expansion equilibrium (i.e. the
relative free energies of the analogous isomers 27vRO, 27vRC and
Next, we examined the ring expansions of cyclic β-ketoesters.
These reactions were the subject of our first two publications in
this area,[5a,b] which focused mainly on the insertion of β-amino
acid derived linear fragments; for example, 5–8- and 12-
membered cyclic β-ketoesters (28) were all found to undergo
smooth ring expansion (to form products of the type 30) upon
reaction under the reported conditions with β-alanine derived acid
chloride 29 (Scheme 5a).[5a] DFT/B3LYP/6-31G* calculations
were performed to measure the energies of the equilibrating
isomers of the 5-, 6-, and 12-membered ring systems 31–33 as
before. Pleasingly, the calculations suggest that the ring
expanded isomers are lowest in energy by a clear margin,
suggesting that there is a strong thermodynamic driving force for
ring expansion in this series (Scheme 5b). To complete the
synthetic series, we went on to perform the ring expansion of 9–
(
2
7vRE are in line with those for the methyl analogue 20, see SI for
[11]
full details) but can be explained by substrate-dependent side
reactions or problems with the preceding N-acylation step. For
example, in the case of furan derivative 27v, the lower yield is
largely due to incomplete N-acylation (step i), which in turn is likely
to be a consequence of the relative instability of the acid-sensitive
furan motif. Unexpected side reactions/degradation also cannot
be ruled out during the ring expansion reaction (step ii) in cases
where more reactive functional groups are involved.
1
1-membered β-ketoesters for the first time, with these new
synthetic reactions proceeding well, affording lactams 34–36 (52–
4%, Scheme 5c).
7
3
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Scheme 6. Ring-size dependency on reaction outcome on the ring expansion
of β-ketoesters with β-hydroxy acid chloride 38. ΔG°rel values are given in
Scheme 5. Ring-size dependency on reaction outcome on the ring expansion
of β-ketoesters with β-alanine derived acid chloride 29. ΔG°rel values are given
in kcal/mol.
kcal/mol.
a
2 2 2 2
i) β-ketoester, 38, MgCl , pyridine, CH Cl , RT; ii) Pd/C H , EtOAc, 3
h, RT; NEt , CHCl , RT, 18 h.
3
3
We then went on to test other lactam-based ring expansion
systems with additional functionality present in the starting
lactams. Hydroxyacid and amino acid derivatives 38 and 46 were
used to exemplify the synthetic reactions, and in the calculations
for 46, a simplified N-methyl (rather than N-benzyl) derivative was
used (i.e. from 47) as this significantly reduced the computational
The hydroxyacid-based analogue of this cyclic β-ketoester ring
expansion was less well developed, with the expansion of 7-
membered 37 the only example of this type featured in our
previous publications to have been performed on a simple cyclic
β-ketoester (Scheme 6a). Given the importance of macrocyclic
lactones in medicinal chemistry,[12] we decided to test whether the
scope of this variant could be expanded. As was done for the
analogous amino acid system, DFT/B3LYP/6-31G* calculations
were performed to measure the energies of the equilibrating
isomers of the 5-, 6-, and 12-membered ring systems 40–42
[13]
time but was found to have very little impact on the calculations.
Thus, we started by examining lactams containing α-heteroatoms
(
3
52, 55, 58 and 60) with amino acid and hydroxyacid derivatives
8 and 46. The analogous heteroatom-free variants of these
reactions had been tested in our earlier work (Scheme 7a) and
were shown to be high yielding. Therefore, based purely on our
chemical intuition at this stage, we did not expect to see much
variation upon switching to these new systems. However, starting
from 6-membered lactam 52, a much lower isolated yield (41%)
of the ring expanded product 53RE was obtained in the amino acid
series, while the ring expanded lactone 54RE was isolated as an
inseparable mixture with its ring-opened imide form 54RO. The
calculations give clues as to why these reactions did not proceed
well; e.g. the ring-opened and ring expanded isomers 53RO and
(
Scheme 6b), which again suggested that there is a clear
thermodynamic driving force for ring expansion. Pleasingly, the
corresponding synthetic experiments all worked well, with 5–8-
membered β-ketoesters undergoing C-acylation, hydrogenolysis
and ring expansion to give ring expanded lactones 39, 40RE, 41RE
and 43 all in comparable yields (Scheme 6c). In a small change
to the published conditions shown in Scheme 6a, we found that
performing the hydrogenolysis in ethyl acetate (rather than
methanol) and then stirring with triethylamine in chloroform led to
superior reaction yields. The main reason the isolated yields are
in the 50—60% range (and not higher) is due to loss of material
during the C-acylation step (especially the work-up, during which
the magnesium salts can cause problems with phase separation)
and these results are in line with typical yields in our previous
papers.[5a,b]
53RE were calculated to have very similar Gibbs free energies,
suggesting that both may be formed in this reaction, although only
the relatively non-polar product 53RE was isolated after
chromatography, in modest yield. Compounds 54RO and 54RE
were also calculated to be similar in free energy and in this case
a mixture of products was isolated. Conversely, upon moving to
7
-membered starting material 55, a clear preference for the ring
expanded isomer was predicted by the calculations, which
manifested in much improved synthetic yields for the desired ring
expanded isomers (70% and 75% for 56RE and 57RE respectively).
4
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Scheme 7. Lactam ring expansion reactions and DFT calculations. ΔG°rel values are given in kcal/mol..
In contrast to oxygen-containing 52 and 55, sulfur-containing
lactams 58 and 60 both performed well in the synthetic ring
expansion reactions with 46;[14] ring expanded products 59RE and
Indeed, the ability to predict when reactions will fail completely is
also important; e.g. the ring opened imide isomer 64RO was
calculated to be the most stable isomer in this series, and this was
corroborated by the synthetic results.
61RE were each formed in good yield. This was again mirrored in
the calculations, with 59RE and 61RE calculated to be the lowest
energy isomers in each case by clear margins. The difference in
reactivity between 52 and 58, which is presumably a result of
some relatively subtle stereoelectronic effects and/or differences
in bond lengths, is not something that we would have predicted
without the calculations.
We also examined benzannulated, fluorinated and
branched lactam starting materials 62, 65, 68 and 70, and as
before, the predictive ability of the calculations was retained.
In general, we have found that for systems in which the ring
expanded isomer is calculated to the lowest in energy by more
than 3 kcal/mol trends, then the reactions tend to work reliably. In
cases where the free energy difference is less than 3 kcal/mol,
the reaction outcomes are less predictable, often giving low yields
of ring expanded products and/or mixtures. The reactions to form
ring expanded products 69RE and 72RE, which were isolated in
modest 30% and 45% yields respectively, are outliers in terms of
yield, but the lower yields in these cases simply reflect the fact
5
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that the N-acylation step did not proceed to completion in either
case. Indeed, an important caveat to keep in mind when using this
DFT/B3LYP/6-31G* method is that it only gives an indication of
the chances of achieving a favourable equilibrium. It does not
account for the efficiency of the synthetic steps that take place
before the equilibrium, the possibility of off-equilibrium side
reactions or other kinetic effects.
Computational chemistry: method evaluation
The
DFT/B3LYP/6-31G*
methodology
used
has
[5d]
demonstrated, in both this and previous work, good success in
predicting the outcome of SuRE reactions. Calculations at the
B3LYP/6-31G* level are relatively computationally efficient, but do
not take into consideration effects such as solvation and
dispersion. These additions are typically used to improve the
accuracy of such calculations, therefore, we decided to
benchmark their effects, along with a range of functionals, in order
to determine any potential method-effects in the calculations.
For this study General Gradient Approximation, GGA
(BP86), hybrid (B3LYP and PBE0) and meta-hybrid (M06 and
M06-2X) functionals were used. Solvation effects were applied
using a PCM model with either dichloromethane or chloroform as
relevant to simulate the reaction conditions. The effects of
dispersion are inherently taken into consideration by the M06 and
M06-2X functionals.[15] They were also applied using the
Grimme’s D3 method with Becke-Johnson damping[16] to a
PBE0/def2-TZVPP single-point calculation, using the geometry
and thermodynamic corrections from a BP86/SV(P) calculation;
this method has been used successfully by our groups in previous
projects,[17] and also tests the effect of a large triple zeta basis
set.[18]
As all the ring expanded products described in this
manuscript were made using SuRE methods, they are all, in
theory, potential starting materials for further ring expansion
reactions. Representative examples of products (73–77) that
have been expanded for a second time in our earlier work are
shown in Figure 1, with the second linear fragment inserted
highlighted in red. After undergoing one ring expansion, the rings
should all be large enough that they are beyond the ‘switch on’
point for any of the ring expansion reaction types that we have
studied and calculated (not withstanding any effects resulting
from the additionally added functional groups) and should
therefore be thermodynamically favourable. This is corroborated
by our work to date in which several successful successive ring
expansion reactions are reported. This does not mean that
performing additional iterations is always routine (e.g. in some
cases, the acylation reactions can be more difficult on these more
functionalised systems, sometimes requiring additional
equivalents of acid chloride),[5c-d] but once acylation has been
achieved, ring expansion is typically straightforward. Three new
examples of doubly ring expanded products (78–80, see SI for
reaction conditions), based on new substrates made for the first
time in this manuscript, have been performed and are reported
here for completeness.
Initially, a wide range of methods were benchmarked
against structures 17–20, by reoptimizing the structures from the
B3LYP/6-31G* calculations and comparing the relative energies
with the experimental outcomes (Table 1). Structures with which
the ring closed isomer has a larger energy than the ring opened
or ring expanded isomers (17, 19 and 20), produced the most
comparable results, with there being little difference when using
GGA or hybrid functionals with the 6-31G* basis set.
Modelling the effects of solvation also had little effect on the
relative energy differences when using the hybrid B3LYP
functional. Comparable results are observed both with and
without solvent corrections. However, this does not extend to the
BP86/SV(P) calculations, with more significant relative energy
differences observed when compared to the standard B3LYP/6-
3
1G* calculations, which appears to come from greater
stabilisation of the ring closed and ring expanded isomers than
the ring opened when solvent is included.
The effects of dispersion had the greatest impact on the
expected outcomes of the experiments, with the M06, M06-2X
and D3(BJ)-PBE0 calculations showing lower relative energies for
the ring closed and ring expanded isomers, predicting that ring
expansion should be comparatively more thermodynamically
favourable in these examples, and in some cases contradicting
the experimental results. We believe that due to the side chain
present in the ring opened structures being directed away from
the ring, there are fewer stabilising interactions present than
compared to the ring closed or expanded isomers. As a
consequence of these different molecule geometries, it appears
that modelling the dispersion interactions may result in the
stability of the ring expanded isomer being overpredicted when
compared to the ring opened form. This alters the expected
reaction outcome where the B3LYP/6-31G* calculations predict
these isomers to be similar in energy.
Figure 1. Successive ring expansion products
6
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Table 1. Relative difference of Gibbs energies at 298 K for structures 17–20 at different levels of theory. Solvent corrections were applied using a PCM model.
Geometry from the BP86/SV(P) level
*
Empirical
Dispersion
Correction
Solvent
Correction
Yield
RE (%)
Compound
Functional
Basis Set
RO (kcal/mol)
RC (kcal/mol)
RE (kcal/mol)
B3LYP
B3LYP
BP86
6-31G*
6-31G*
N
N
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
16.5
14.9
14.9
14.1
10.8
8.7
1.9
0.2
PCM
N
N
6-31G*
N
1.6
PBE0
M06
6-31G*
N
N
1.2
17 (n = 1)
18 (n = 2)
19 (n = 3)
20 (n = 4)
0
6-31G*
PCM
PCM
PCM
PCM
N
N
-2.1
-1.6
-2.1
-3.3
M06-2X
BP86
6-31G*
SV(P)
N
11.5
9.2
PBE0*
def2-TZVPP
D3(BJ)
B3LYP
B3LYP
BP86
6-31G*
6-31G*
N
N
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
3.9
2.2
2.1
-1.1
-1.1
-1.6
-3.8
-4.1
-3.0
-5.3
PCM
N
N
6-31G*
N
0.5
PBE0
M06
6-31G*
N
N
-0.6
-3.0
-4.5
-1.2
-3.0
0
6-31G*
PCM
PCM
PCM
PCM
N
N
M06-2X
BP86
6-31G*
SV(P)
N
PBE0*
def2-TZVPP
D3(BJ)
B3LYP
B3LYP
BP86
6-31G*
6-31G*
N
N
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
6.4
6.2
5.5
4.4
1.1
-0.5
2.7
0.7
0.7
-0.3
-0.4
-1.3
-3.8
-3.4
-1.8
-5.0
PCM
N
N
6-31G*
N
PBE0
M06
6-31G*
N
N
0
6-31G*
PCM
PCM
PCM
PCM
N
N
M06-2X
BP86
6-31G*
SV(P)
N
PBE0*
def2-TZVPP
D3(BJ)
B3LYP
B3LYP
BP86
6-31G*
6-31G*
N
N
7.3
9.9
14.1
16.1
13.8
13.3
12.8
10.5
13.6
14.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
PCM
N
N
6-31G*
N
8.3
PBE0
M06
6-31G*
N
N
8.8
82
6-31G*
PCM
PCM
PCM
PCM
N
N
12.2
11.4
11.1
13.4
M06-2X
BP86
6-31G*
SV(P)
N
PBE0*
def2-TZVPP
D3(BJ)
7
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Table 2. Relative difference of Gibbs energies at 298 K. Solvent corrections were applied using a PCM model with either dichloromethane or chloroform as relevant
-1
for the M06-2X/6-31G* calculations. See ESI for absolute energies. Blue shading denotes the most significant differences between the two methods > 3 kcal mol .
ave is defined as the mean value of the energy at M06-2X/6-31G* - energy at B3LYP/6-31G*. aIsolated as a mixture (4:3 54RE:54RO).

Compound
Functional/basis set
RO (kcal/mol)
RC (kcal/mol)
RE (kcal/mol)
Yield RE (%)
75a
31
B3LYP/6-31G*
M06-2X/6-31G*
10.0
12.5
12.6
10.2
0.0
0.0
6
B3LYP/6-31G*
M06-2X/6-31G*
8.1
9.7
3.7
0.0
0.0
32
33
40
41
42
53
54
56
57
59
61
63
64
66
67
69
71
72
825a
805a
59
56
-
10.5
B3LYP/6-31G*
M06-2X/6-31G*
36.6
38.0
45.4
34.7
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
9.3
11.8
8.1
0.0
0.0
11.7
B3LYP/6-31G*
M06-2X/6-31G*
10.8
10.3
10.3
3.7
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
35.2
32.6
39.8
30.5
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
0.0
6.9
9.7
7.1
0.0
0.0
41
67a
70
75
99
73
40
0
B3LYP/6-31G*
M06-2X/6-31G*
2.9
5.0
9.2
4.5
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
5.5
17.9
13.8
0.0
0.0
11.7
B3LYP/6-31G*
M06-2X/6-31G*
10.4
11.2
19.6
13.8
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
6.7
18.4
13.1
0.0
0.0
12.0
B3LYP/6-31G*
M06-2X/6-31G*
10.9
14.5
20.3
15.1
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
-2.5
2.8
13.4
10.0
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
-3.3
0.5
10.6
6.8
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
5.9
9.4
24.2
19.1
0.0
0.0
77
71
30
84
45
B3LYP/6-31G*
M06-2X/6-31G*
3.9
6.0
17.7
12.8
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
3.9
9.2
11.2
5.7
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
3.5
9.8
19.6
14.5
0.0
0.0
B3LYP/6-31G*
M06-2X/6-31G*
4.8
6.6
3.1
14.5
9.2
0.0
0.0
0.0

ave
-5.2
8
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Chemistry - A European Journal
10.1002/chem.202002164
FULL PAPER
With dispersion effects having a large effect on the relative energy
differences and the predicted thermodynamic outcomes on these
examples, the study was extended to include these effects to
several other systems, using the M06-2X/6-31G* methodology. A
comparison between this method and B3LYP/6-31G* is
presented in Table 2. As observed with structures 17–20 (Table
rule. However, as a guide to assess the viability of new ring
expansion reactions before embarking on synthetic effort, we do
believe that this DFT/B3LYP/6-31G* method, which is widely
implemented across the vast majority of computational chemistry
packages, has practical utility and will be useful in directing future
synthetic efforts, in our group and others.
1
), the main difference between the two methods is that, when
compared to the ring expanded form, the relative energies of the
ring closed forms are lower at the M06-2X/6-31G* level (ave = –
Acknowledgements
5
.2 kcal/mol), and ring opened isomers increased (ave = 3.1
kcal/mol). In most instances this doesn’t change the expected
outcome of the reaction, however, where there is a smaller
difference in the energy of the ring opened and ring expanded
isomers (see 53, 63 and 64), this does result in ring expansion
being predicted to be favourable. Notably in some examples the
intermediate ring closed isomer becomes lower in energy than the
ring opened, however, this does not seem to correlate to any
observable difference in how well the reaction proceeds
experimentally (see 32, 40 and 69 for examples).
Thus, for either method, both the B3LYP and M06-2X
functionals correctly predicts the expected reaction outcomes in
the majority of cases, although on average, it is the B3LYP
method that more closely correlates with the experimental
findings, despite the fact that the M06-2X functional usually
The authors thank the Leverhulme Trust (for an Early Career
Fellowship, ECF-2015-013, for W. P. U.) the University of York (T.
C. S., K. Y. P., J. K. S., W. P. U.) and the EPSRC (EP/P029795/1,
A. L., and for the computational equipment used in this study,
grants EP/H011455/1 and EP/K031589/1)) for financial support.
We are also grateful to the Science and Engineering Research
Board, Department of Science & Technology, Government of
India for an overseas postdoctoral fellowship for M. L., to
Erasmus+ for supporting E. M., and the Department of Chemistry,
University of York for the provision of an Eleanor Dodson
Fellowship (to W. P. U.). Finally, thanks also go to Prof Paul
Clarke (University of York) for assistance with Spartan.
Keywords: rearrangement • macrocycle • medium-sized ring •
ring expansion • DFT
performs better for organic molecules due to the inclusion of
dispersion corrections.[15,19] Therefore, we believe that these
results clearly demonstrate that the B3LYP/6-31G* methodology
is suitable as an aid for predicting the outcome of SuRE reactions,
balancing computational efficiency with good prediction of
reaction outcome. The observation that a greater than 3 kcal/mol
energy difference between ring opened and ring expanded
isomers is needed to more confidently predict the outcome of the
reaction, is based upon the inherent computational accuracy of
these calculations
[
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2
In summary, we have significantly expanded the scope of various
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4
8 new ring expanded products are reported in this manuscript.
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In most cases, the isomer calculated to be lowest in energy was
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may prevent equilibrium being reached in some reaction systems,
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predictions on reaction yields or the Boltzmann distribution of the
isomers in the presumed equilibria. The guideline that a free
energy difference of more than 3 kcal/mol in favour of the ring
expanded isomer when using the B3LYP/6-31G* methodology
usually leads to a successful reaction is a qualitative observation,
that this was true in all such cases tested in which the preceding
acylation step was efficient. It should not be considered a hard
1
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Chemistry - A European Journal
10.1002/chem.202002164
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all three of the calculated ΔGrel° values were within 0.7 kcal/mol of the
simplified analogues: ΔGrel° values for 53 calculated using the standard
DFT/B3LYP/6-31G* method: 53RO (imide) = 0.0 kcal/mol; 53RC (cyclol) =
10.4 kcal/mol; 53vRE (ring expanded) = 0.3 kcal/mol.
[
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6]
The DFT/B3LYP/6-31G* method was chosen as it is well known,
implemented across the vast majority of computational chemistry
packages, and it performs well in various settings, including in our earlier
work (reference 5d).
[
[
7]
8]
B3LYP, BP86, PBE0, M06 and M06-2X functionals and 6-31G*, SV(P)
and def2-TZVPP basis sets have all been evaluated in this study. See
Tables 1 and 2 and ESI and the associated discussion for details.
The energy calculations, final optimisations and frequency calculations
were all done in a vacuum. In our previous study (reference 5d) all the
calculations were run using a solvated model system (non-polar solvent)
as well as in vacuum, and there was little difference in the free energy
values obtained between the two methods, therefore it was decided to
use vacuum calculations in this study, given that they are less demanding
computationally.
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[
[
11] ΔGrel° values for 27v calculated using the standard DFT/B3LYP/6-
1G*method (see SI for full details): 27vRO (imide) = 8.1 kcal/mol; 27vRC
cyclol) = 16.7 kcal/mol; 27vRE (ring expanded) = 0.0 kcal/mol
3
(
12] (a) J. M. Mcguire, R. I. Bunch, R. C. Anderson, H. E. Boaz, E. H. Flynn,
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1
0
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
Ring expansion reactions based on amino/hydroxyacid side chain insertion are strongly dependent on ring size. This manuscript
details efforts to provide guidelines on which ring systems are more likely to be successful. The synthetic results are supported by
computational chemistry, using Density Functional Theory. Calculating the relative Gibbs free energies of three isomeric species
formed during ring expansion enables the viability of new reactions to be correctly predicted in most cases.
Institute and/or researcher Twitter usernames: @ChemistryatYork, @UnsworthChem, @Dr_Katie_J_Lamb
1
1
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