The influence of distal substitution on the base-induced isomerization of long-chain terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2017.09.026

When compared to a long-straight chain terminal alkyne, a long chain terminal alkyne with a distal isopropyl unit (isobranched) isomerizes about two times faster when treated with strong base under identical conditions, and appears to follow pseudo first order kinetics. In both cases, equilibration to a 95–97:5–3 mixture of terminal:internal alkyne accompanies isomerization. The difference in rate may be due to an unusual folding of both long-chain alkynes, bringing the distal substituent close to the carbon-carbon-triple bond moiety. The distal isopropyl moiety may provide unanticipated steric hindrance that disrupts such folding, making the propargylic proton more available for reaction with base.

Full text of DOI:10.1016/j.tetlet.2017.09.026

Accepted Manuscript
The influence of distal substitution on the base-induced isomerization of long-
chain terminal alkynes
Innus Mohammad, JiYoung Mun, Amber Onorato, Martha D. Morton, Abdullah
I. Saleh, Michael.B. Smith
PII:
S0040-4039(17)31155-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.026
TETL 49296
Reference:
Tetrahedron Letters
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7 September 2017
13 September 2017
Please cite this article as: Mohammad, I., Mun, J., Onorato, A., Morton, M.D., Saleh, A.I., Smith, Michael.B., The
influence of distal substitution on the base-induced isomerization of long-chain terminal alkynes, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.09.026
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Graphical Abstract
.
The influence of distal substitution on the
base-induced isomerization of long-chain
terminal alkynes
Leave this area blank for abstract info.
Innus Mohammad, Ji-Young Mun, Amber Onorato, Martha D. Morton, Abdullah I. Saleh, and Michael B.
Smith*

1
Tetrahedron Letters
The influence of distal substitution on the base-induced isomerization of long-chain
terminal alkynes
Innus Mohammad, JiYoung Mun,, Amber Onorato,, Martha D. Morton, Abdullah I. Saleh, and Michael. B.

Smith
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269-3060, USA
ARTICLE INFO
ABSTRACT
When compared to a long-straight chain terminal alkyne, a long chain terminal alkyne
Article history:
Received
Received in revised form
Accepted
with a distal isopropyl unit (isobranched) isomerizes about two times faster when treated with
strong base under identical conditions, and appears to follow pseudo first order kinetics. In both
cases, equilibration to a 95-97:5-3 mixture of terminal:internal alkyne accompanies
isomerization. The difference in rate may be due to an unusual folding of both long-chain
Available online
alkynes, bringing the distal substituent close to the carbon-carbon-triple bond moiety. The distal
isopropyl moiety may provide unanticipated steric hindrance that disrupts such folding, making
the propargylic proton more available for reaction with base.
Keywords:
alkyne
kinetics
isomerization
distal isobranch
allene
2009 Elsevier Ltd. All rights reserved.
———
 Michael B. Smith +1-860-486-2881; fax: +1-860-486-2981; e-mail: michael.smith@uconn.edu

2
1
INTRODUCTION
Inflammatory periodontal disease in adults is initiated
dipeptide lipid classes in P. gingivalis that comprise a new class
4
with the accumulation of specific bacteria in the sulcus around
the teeth, followed by a chronic inflammatory reaction by the
host against the colonizing microorganisms. The anaerobic
Gram-negative organism, Porphyromonas gingivalis, is thought
of ligands (see 2 and 3) for Toll-like receptor 2 (TLR2). These
agonists are also produced by common oral and intestinal
5
Bacteroidetes, and they are recovered in chronically inflamed
human tissues including destructive periodontal disease and
1
to be a major periodontal pathogen associated with destructive
2
atherosclerosis tissues.
periodontal disease in adults. P. gingivalis and other
phylogenetically related organisms produce a variety of novel
The base-induced isomerization of the triple bond of
6
terminal alkynes is well known, proceeding through an allene
2
lipids, including phosphorylated dihydroceramide lipids (see
7
intermediate. This isomerization typically requires a strong base
3
1). More recent work in our laboratories identified serine
and KOH in alcohol, but sodium amide in DMSO has been
of 1-4% of pent-1-yne, with some penta-1-2,diene.
In previous work, we synthesized the putative C17 and
C19 dihydroceramides to prove their structure and showed that
4,11
8
used. Small amounts of the allene were sometimes isolated
9
during the isomerization reaction although the allene was prone
the long aliphatic chain terminated in an isopropyl unit,
and
to polymerization and was not always detected. In another
10
that this terminal isopropyl unit is critical for expression of the
study, a mechanism for the isomerization of pent-1-yne was
12
biological activity. A terminal isopropyl unit in a long
proposed, using KOH in ethanol, in a sealed tube at 175 °C,
aliphatic chain is hereafter referred to as an isobranch. We
deprotonation led to allene formation, which led to the
13,14
6a
recently reported the convergent synthesis of 2 and 3.
thermodynamically more stable internal alkyne, pent-2-yne.
Analysis of the products for this latter study showed the presence
Scheme 1. Synthesis of alkynes 5 and 9
This synthesis began with a lithium tetrachlorocuprate-mediated
coupling reaction of the Grignard reagent prepared in situ by
reaction of 1-bromo-2-methylpropane with commercially
available 11-bromoundecan-1-ol (6), which gave 13-
methyltetradecan-1-ol (7) in 79 % yield. Conversion to the
bromide (8) with NBS and PPh3 (81 % yield) was followed by
reaction with lithium acetylide to give 15-methylhexadec-1-yne
(9) in 77 % yield.
2 RESULTS AND DISCUSSION
To determine the kinetics of base-induced
isomerization, we required an unambiguous synthesis of both the
straight-chain alkyne (5) and the distal isobranched terminal
alkyne (9). The synthesis of the straight-chain alkyne proceeded
without problem, via coupling of lithium acetylide with
commercially available 1-bromohexadecane (4), in dry DMSO,
to give octadec-1-yne (1) in 73 % yield. We prepared the
isobranched intermediate, 13-methyl-1-bromotetradecan-1-ol (7),
The kinetics for both 5 and 9 were obtained in DMSO
at 55 °C and also at 75 °C, temperatures at which reasonable data
15
16
using, in part, methodology reported by Singh and by Mori.
17
could be collected.
Samples were prepared that were 0.042 M

3
alkyne in DMSO. Potassium tert-butoxide was added to each
sample and aliquots were removed at the time intervals shown in
Figures 1 and 2, quenched with water, the products extracted
with hexane, and 1H NMR was used to monitor the reaction.
We plotted [alkyne] vs. time, ln [alkyne] vs. time and
reaction for all rate constants reported herein. This observation
is reasonable if one of the reactants, possibly the base, is in
excess relative to the deprotonation reaction with the alkyne.
Figure 1 shows a comparison of the reactions of 5 and 9 at 55 °C
and 75 °C. Figure 2 shows the changes in rate at 55 °C and at 75
°C for 5 and for 9.
1/[alkyne] vs. time, but the linear plots were obtained only for ln
[alkyne] vs. time. Our results point to a pseudo first order
5
9
ln [alkyne] at 55 °C
ln [alkyne] at 75 °C
Figure 1. Plot of ln [5] and ln [9] vs. time (min.) at both 55 °C and 75 °C.
Based on the results in Figures 1 and 2, it is clear that
isomerization of the isobranched alkyne is faster than that of the
straight-chain alkyne. However our results also show that for
both 5 and 9, the isomerization does not go to completion, but
rather reaches an equilibrium of about 95-97% internal + 3-5%
terminal alkyne. Indeed, we observed a late-reaction change in
rate data that we believe reflects the point where this equilibrium
is reached. The plots in Figure 1 and 2 only show the rate data
pertinent to the isomerization, and do not show this equilibrium
that occurred only after extended reaction times. We did not
observe signals in the 1H NMR that correspond to the presence of
9,10
allene or the alk-3-yne,
out their presence.
although we cannot completely rule
5
9
ln [5] at 55 °C and 75 °C
ln [9] at 55 °C and 75 °C.
Figure 2. Plot of ln [5] at 55 °C and 75 °C and ln [9] at 55 °C and 75 °C vs. time (min).

4
18
We calculated a rate constant at 55 °C using the slope
conformation. Bohn’s work with relatively short chain alkynes
of the lines seen in Figures 1 and 2 and obtained a value of -
4.403 x 10-3 mol-1 min-1 for the isobranched alkyne (9) and -2.075
x 10-3 mol-1 min-1 for the straight chain alkyne (5). A similar plot
done at 75 °C is shown in Figures 1 and 2, and gave a rate of -
2.27 x 10-2 mol-1 min-1 for 9 and 1.702 x 10-2 mol-1 min-1 for 5.
Calculations showed that Ea for 9 = –9.63 x 10-4 J mol-1, and Ea
for 5 = –2.88 x 10-4 J mol-1. The results of our calculations for
the pseudo first-order rate constants and the activation energies
are shown in Table 1
raises a point that may be relevant to our work. Microwave
spectroscopic analysis of several alkynes presented evidence or
the presence of an intramolecular CH/-interaction that stabilized
18
gauche conformations relative to more open conformations. It
is, therefore, possible that long-chain alkynes exist in folded or
coiled conformations in relatively large percentages, especially if
19
there is an aggregation effect. Rebek’s work has shown that a
series of normal alkanes (C16 to C19) assume coiled, compressed
conformations in small spaces. Specifically, the alkanes were
encapsulated in self-assembled, hydrogen-bonded complexes. It
is also known that alkanes are folded when encapsulated in
The faster rate of isomerization for 9 relative to 5 is
clear, and there is a lower activation barrier for the reaction. The
real question is why does a methyl group at the end of a long
carbon chain have an influence of the rate of a reaction at the
other end of the molecule? It is reasonable to assume that
difference in rate is likely due to aggregation of the alkyne
molecules that makes the isobranched alkyne more available for
deprotonation reaction with the base. An alternative is that this
effect may be an intramolecular interaction related to
20
21
resorcinarene or pyrogallolarene. Putative aggregation
effects or intramolecular interactions may affect the conformation
of long-chain alkynes and contribute to the observed rate
differences for 5 and 9. Simple energy calculations for coiled
conformations of 5 and of 9 indicated that coiled 9 was about 2.4
kJ higher in energy.
Table 1. . Pseudo first-order rate constants and activation energies for 5 and 9
Alkyne
Pseudo First Order Rate Constant
Pseudo First Order Rate Constant
Activation Energy
J mol
-1
-1
-1
-1
-1
(55 °C) Mol min
(75 °C) Mol min
5
9
-2.075 x 10-3
-1.702 x 10-2
-2.88 x 10-4
-9.63 x 10-4
-4.403 x 10-3
-2.271 x 10-2
determined that 4.38% of water was present in the DMSO and
the water may exacerbate this effect or even promote it. It is also
possible that the polar DMSO may induce or enhance a dipole-
We determined the water content in the DMSO used in
22
this study using a Karl Fisher Coulometer, which was found to
be 4.38%. Similar analysis with a freshly opened bottle of
DMSO was up to 1%. Our experiments with the ‘dry’ DMSO
showed little difference in the rate of isomerization of 1 and of 2.
Clearly, the water plays a role in the difference in isomerization,
perhaps increasing the polarity of the solvent relative to the
alkyne and putative aggregation or conformational effects,
although the role of the water is not clear.
23
induced dipole in the alkyne. There is no reason to believe that
the base would interact differently with alkynes 5 and 9 in the
absence of external factors. Such an effect may be common in
long-chain species since differences in reactivity are common
between long chain and short chain compounds.
ACKNOWLEDGMENTS
The authors would like to thank Dr. You-Jun Fu for
his assistance in obtaining the mass spectral data.
3 CONCLUSIONS
We have shown that a distal isobranch in a long-chain
terminal alkyne influences the rate of isomerization to an internal
alkyne. Indeed, we have shown that alkyne 9 isomerizes 2.1
times faster than alkyne 1 at 55 °C, and alkyne 5 isomerizes 1.33
times faster than alkyne 5 at 75 °C. We speculate that coiling in
long-chain alkynes, perhaps due to aggregation effects, is
operative in the DMSO solvent and that the distal isobranch
disrupts the coiling sufficiently to allow more rapid
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A. Supplementary Material
Supplementary data associated with this article can be found, in
the online version, at.