Remarkable Solvent Effects of Structurally Diverse Alcohols on Nucleophilic Displacement Reactions with Halide Ions

Full text of DOI:10.1002/bkcs.11496

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DOI: 10.1002/bkcs.11496
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B. S. Moon et al.
KOREAN CHEMICAL SOCIETY
Remarkable Solvent Effects of Structurally Diverse Alcohols on
Nucleophilic Displacement Reactions with Halide Ions
†
‡,*
‡
§
‡,¶,*
Byung Seok Moon, Byoung Se Lee, So Young Chu, Dong Wook Kim, and Dae Yoon Chi
†
Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea
‡
Research Institute of Labeling, FutureChem Co. Ltd, Seoul 01811, Korea.
*
E-mail: byoungse.lee@futurechem.co.kr
§
Department of Chemistry, Inha University, Incheon 22212, Korea
¶
Department of Chemistry, Sogang University, Seoul 04107, Korea. *E-mail: dychi@sogang.ac.kr
Received April 16, 2018, Accepted May 21, 2018
Keywords: Fluoride, Nucleophilic substitution, Hydrogen bonding, Solvent effect, Solvent polarity
Nucleophilic displacement reactions with halide ions are a
well-known and widely studied functional group transfor-
mation in organic chemistry. Among halide ions, fluoride
ion has received considerable attention because of its
diverse utilization in the synthesis of fluorinated products
for medicinal chemistry, materials science, and medical
be described for a general understanding of this solvent
effect.
For this study, nine different alcohols, including primary,
secondary, and tertiary alcohols, were chosen as solvents for
nucleophilic displacement reactions with halide ions: metha-
nol (MeOH), ethanol (EtOH), and n-propanol (n-PrOH) were
chosen as primary alcohols; 2-propanol (i-PrOH), 3-pentanol
1
imaging. Fluoride-18 as a positron emitter is an especially
attractive radioisotope for positron emission tomography
(3-PnOH), and 2,4-dimethyl-3-pentanol (2,4-Me –3-PnOH)
2
(
PET), due to its manageable half-life (t1/2 = 110 min) and
were secondary alcohols; and tert-butyl alcohol (t-BuOH),
tert-amyl alcohol (t-Amyl-OH), and 3-ethyl-3-pentanol (3-Et-
3-PnOH) were the tertiary alcohols. Acetonitrile was selected
as an aprotic polar solvent for comparison. The polarity of
these solvents roughly follows the order of primary > sec-
ondary > tertiary, which typically is reduced as the molecular
2
in-house production using a medical cyclotron.
In 2006, we made a significant discovery regarding the
chemoselective nucleophilic fluorination in tertiary alcohol
3
solvents. Fluorination of various model compounds using
CsF in tertiary alcohols gave the corresponding fluorinated
products in good to excellent yields with a minimal amount
of olefin byproduct. We suggested that this enhanced selec-
tivity results from hydrogen bonding between the fluoride
ion and the tertiary alcohol solvent. Nucleophilic fluorina-
tion is conventionally carried out in aprotic solvents such
as acetonitrile, acetone, DMF, and DMSO to avoid the
hydrogen bonding interaction between fluoride and solvent
molecules, which reduces the nucleophilicity of fluoride
6
mass increase. The nucleophilic displacement reaction of
2-(3-methanesulfonyloxypropoxy)naphthalene (1) with tetra-
n-butylammonium halides was chosen as the standard reac-
tion. Notably, alcohol solvents can interact with the sulfonate
leaving group and facilitate its departure while stabilizing its
3
3,5f
charge. In previous studies,
excess alkali metal halides
have been used as halide sources to compare reactivity under
diverse conditions. However, alkali metal salts have quite
low solubility and a low reactivity in organic solvents with-
out phase-transfer catalysts such as cryptands or tetraalkylam-
4
ions. Since publication of the result, several successive
studies and successful applications to fluorine-18 labeled
PET radiotracers have been reported. The influence of ter-
5
7
monium salts. The observed reaction rate reflects the
tiary alcohols on nucleophilic fluorination was primarily
explained by the relatively weak hydrogen bonding com-
pared with primary alcohol solvents such as methanol and
ethanol, due to steric bulkiness and reduced hydroxyl
acidity. In addition, alcohol solvents can interact with a sul-
fonate leaving group to facilitate its departure by stabilizing
the developing charge. However, despite enhanced chemos-
electivity in tertiary alcohols, the reactivity of fluoride ions
is still lower than in polar aprotic solvents. In this paper,
we account for the improvement of reactivity in bulky pro-
tic solvent in terms of “solvent polarity” and suggest better
reaction media for rapid nucleophilic fluorinations that con-
serve chemoselectivity. Other nucleophilic displacement
reactions with chloride, bromide, and iodide ions will also
following two steps: polar ionic nucleophiles are first sol-
vated in the reaction medium via catalytic cycling of com-
plexation/ion exchange with a phase-transfer catalyst, then
8
nucleophilic displacement occurs. Since the solvation step is
usually slower, the observed reaction rate mainly depends on
the solvation rather than nucleophilic displacement. The solu-
bility of alkali metal halides can be also dependent on the
9
reaction medium. Therefore, to avoid such a distortion of
results caused by solvation of halide salts in the reaction
media, a series of tetra-n-butylammonium halides (TBAX)
was used as good soluble halide sources. In addition, for the
convenience of calculations, all substitutions were induced to
behave as approximately pseudo-first order reactions by
using 10 equiv. of TBAX for each reaction (Scheme 1).
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O
OMs
O
X
as well as nucleophilicity in acetonitrile, this reaction afforded
an olefin by-product via E2 elimination despite having the
fastest substitution reaction rate. As shown in Figure 1(a), the
fluorination in acetonitrile finished quickly to yield 92% of
the fluorinated product as well as 8% of olefin byproduct.
The chlorination reaction proceeds with a more limited
influence of hydrogen bonding. Therefore, the chlorination
reaction rate in alcohol solvents considerably increases with
a similar pattern found for the fluorination (Figure 1(b) and
Table S1, Supporting Information). The chlorination in the
TBAX
solvent
0 oC, 2 h
1
2a, X = F
2
2
2
6
b, X = Cl
c, X = Br
d, X = I
Scheme 1. Nucleophilic displacement reaction of 1 with tetra-n-
butylammonium halides.
The reaction progress was determined by HPLC analysis at
various time intervals (5, 10, 20, 40, 60, 90, and 120 min).
Only trace amounts of byproducts (less than 1%) were
detected in alcohol solvents. The observed rate constant
kobs) was obtained for each reaction using the GraphPad
ver. 4.0) program with one-phase exponential association.
secondary alcohol 2,3-Me -3-PnOH is also faster than in
2
t-BuOH and t-Amyl-OH. Moreover, the chlorination pro-
ceeds faster in 3-Et-3-PnOH, the most bulky alcohol solvent
in the study, than even in acetonitrile—because dipolar ace-
tonitrile interacts more strongly with the larger, more polariz-
able chloride ion compared with fluoride ion. An olefin
byproduct is not observed for chlorination in acetonitrile.
Hydrogen bonding between bromide ions and alcohol is
negligible in the bromination reaction, which results in fas-
ter conversions than either fluorination or chlorination
(Figure 1(c), Table S1). As was the case for fluorination
and chlorination, the observed bromination reaction rate is
found to increase in bulky alcohol media. In acetonitrile,
the rate of bromination decreases largely due to the signifi-
cantly higher ion-dipole interaction when compared with
fluorination and chlorination reactions.
(
(
Subsequently, the relative rate constant (k ) was calculated
rel
based on the slowest reaction, i.e., fluorination in MeOH.
In alcohol solvents, the reaction rate is thought to mainly
depend on the ability of the solvent to participate in hydrogen
bonding. From the point of view of electronic factors, elec-
tron donating alkyl groups make alcoholic O H groups less
acidic, which results in weaker hydrogen bonding interactions.
In addition, alkyl substituents can play a role in disturbing the
hydrogen bond via steric hindrance. In this regard, the
observed rate of fluorination generally increases in the order
primary < secondary < tertiary alcohol as shown in Figure 1.
3,5
One of the secondary alcohols, 2,4-Me -3-PnOH, however,
2
achieved more reactive fluorination than two tertiary alcohols,
t-BuOH and t-Amyl-OH, which is probably due to the two
bulky diisopropyl groups. The fluorination reaction in acetoni-
trile proceeds faster than in any of the alcohol solvents
because the aprotic acetonitrile solvent does not interact with
the fluoride nucleophile. In addition, due to its strong basicity
The iodide ions, the most polarizable ion, does not form
hydrogen bonds with alcohol solvent molecules, and nucle-
ophilic iodination in alcohols exhibits the fastest conver-
sions among the four nucleophilic halogenation reactions
(Figure 1(d), Table S1). The iodination reaction proceeds
approximately 10-fold faster in methanol compared to
(
A)
(B)
1
00
100
75
50
25
0
7
5
2
5
0
5
0
0
30
60
90
120
0
30
60
90
120
Time (min)
Time (min)
(
C)
(D)
1
00
100
75
50
25
0
7
5
2
5
0
5
0
0
30
60
90
120
0
30
60
90
120
Time (min)
Time (min)
Figure 1. Reaction curves in various solvents: (a) fluorination, (b) chlorination, (c) bromination, (d) iodination. Each symbol means MeOH
), EtOH ( ), n-PrOH ( ), i-PrOH ( ), 3-PnOH ( ), 2,4-Me –3-PnOH ( ), t-BuOH ( ), t-Amyl-OH ( ), 3-Et-3-PnOH ( ), and MeCN ( ).
(
2
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KOREAN CHEMICAL SOCIETY
fluorination. Iodination in alcohols also maintains the same
order of reactivity as the other halide displacements. Unex-
pectedly, iodination in the two bulky solvents 2,4-Me2-
well as more than 400 pure organic solvents (including
many alcohols) in the range from 0.00 (tetramethylsilane)
12
to 1.00 (water). On this scale, the larger the alkyl substit-
N
3-PnOH and 3-Et-3-PnOH proceeds slightly slower than
uent, the lower the ET value of an alcohol as indicated by
the bromination or chlorination reactions. A slow iodination
reaction rate was also observed in acetonitrile due to a sig-
nificant ion-dipole interaction.
the following values: MeOH, 0.762; EtOH, 0.654; n-PrOH,
0.617; i-PrOH, 0.546; 3-PnOH, 0.463; t-BuOH, 0.389; t-
Amyl-OH, 0.318; 2,4-Me -3-PnOH, 0.290; 3-Et-3-PnOH,
2
13,14
Figure 2 illustrates a comparison of reaction rates for the
four halide displacement reactions with respect to each sol-
vent. As expected, in MeCN, an aprotic medium, the order
0.241. Based on Hughes and Ingold’s parameter,
we
investigated the correlation of the relative reaction rates
N
T
with the normalized solvent polarity E . It is found that the
−
−
−
−
of nucleophilicity for halide ions is F > Cl > Br > I ,
whereas the larger halide ions roughly exhibits better nucle-
ophilicity in alcohol solvents. It is notable that in the nucle-
ophilic fluorination reaction, among the various alcohol
solvents, more sterically demanding bulky alcohol solvents
greatly increase the reaction rate, and these tendencies are
reaction rates tend to increase exponentially in inverse pro-
portion to the corresponding ET value, as shown Figure 3,
except for iodination due to the considerable stabilization
that resulting from interactions between the polarizable,
large iodide ion with bulky alcohol solvents. This correla-
N
tion data can explain why the reactivity in 2,4-Me -3-PnOH
2
3
,5f
consistent with those of previous studies
in which the
is higher than that found in the tertiary alcohol solvents t-
BuOH and t-Amyl-OH despite being a secondary alcohol.
Analysis of the results based on Hughes and Ingold’s rule
seems to more accurately reproduce the results than simply
examining them through the perspective of hydrogen bond-
ing. It should be noted that solvent polarity is a complex
property that includes dipole moment (μ), relative permittiv-
enhanced nucleophilicity of fluoride ions was explained by
−
the weaker HÁ Á ÁF hydrogen-bond interaction caused by
the lower acidity and steric bulkiness of tertiary alcohols.
However, despite the other halides have little or no capabil-
ity to participate in hydrogen bonding, the other halogena-
tion reactions showed similar trends as the fluorination in
alcohol media shown in Figure 2. Previous suppositions for
the enhanced reactivity of fluorination in alcohol solvents
are not sufficient to explain the other nucleophilic halide
ion displacements, which also proceeds well in bulky alco-
hol solvents. Therefore, we can conclude that there must be
a different dynamic at play beyond hydrogen bonding.
The nucleophilic halide displacement reactions in this study
ity (ε ), solubility, hydrogen bonding, etc. Thus, the ability
τ
to hydrogen-bond is only one of various descriptors for
determining solvent polarity. Although the rate of fluorina-
tion exhibits a good correlation with Kamlet and Taft’s
15
hydrogen-bond donor parameter α, the α value is not able
to be adapted to other nucleophilic halide displacements.
The influence of hydrogen bonding on the fluorination in
alcohol solvents can be estimated by comparing two solvents,
proceed via the S 2 mechanism. In the transition state, the
N
halide ion’s negative charge is dispersed through the whole
transition-state complex, which makes the delocalized nega-
tive charge less effective. Therefore, the reaction proceeds fas-
ter in less polar solvents by destabilization of the initial state
with a higher charge density at the halide ion, as compared to
the corresponding transition state with a delocalized charge.
N
N
3
-PnOH (E = 0.463) and acetonitrile (E = 0.460). The
T
T
fluorination reaction is slower by a factor of 9.5 in 3-PnOH
than in acetonitrile even though these solvents have similar
polarities, which indicates that hydrogen bonding is the pre-
dominant factor during fluorination. Conversely, iodination
is slower by a factor of 3.6 in acetonitrile than in 3-PnOH
because there is some stabilization that results from interac-
tions between the polarizable, large iodide ions and dipolar
The E (30) scale is an extremely useful, empirical solvent
T
10
N
6
T
polarity scale, which is frequently normalized to E : This
scale covers a large number of binary solvent mixtures as
11
3
-Et-3-PnOH
1000
2
,4-Me -3-PnOH
2
I
8
00
00
00
00
0
Br
Cl
F
t-Amyl-OH
6
4
2
t-BuOH
3
-PnOH
i-PrOH
n-PrOH
EtOH
MeOH
0.8
0.7
0.6
0.5
0.4
0.3
0.2
normalized solvent polarity
polar
nonpolar
Figure 2. Comparison graph of reaction rate of each halide ion in
various alcoholic solvents.
Figure 3. Correlation between reaction rates and the normalized
N
solvent polarity parameter E .
T
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BULLETIN OF THE
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KOREAN CHEMICAL SOCIETY
3
0
acetonitrile (dipole moment, μ = 13.0 × 10 /CÁm) com-
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Acknowledgments. The research was supported by the
National Research Foundation of Korea (NRF) grants
(2016M2A2A7A03913537, 2016M2B2A4911049, 2015R1-
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