Bridge-Chlorinated Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acids

Article abstract of DOI:10.1021/acs.joc.8b02780

Radical chlorination of bicyclo[1.1.1]pentane-1,3-dicarboxylic acid is highly selective, and up to four chlorine atoms can be introduced relatively easily without damage to the strained bicyclic cage. Combined with hydrodechlorination with TMS₃SiH, direct chlorination provides access to five of the 15 possible chlorinated diacids. Their configuration has been established by X-ray diffraction. Their pK_a values have been measured by capillary electrophoresis and calculated at the B3LYP-D3BJ/6-311+G(d,p)-level. The results are in good agreement and reflect the expected trend, from 2.78 ± 0.08 and 4.14 ± 0.10 in the parent to 1.07 ± 0.03 and 2.31 ± 0.03 in the tetrachlorinated diacid. Strain energy relative to the parent diacid was calculated for all 15 chlorinated diacids and shows a dramatic increase with successive chlorination, due to nonbonded Cl-Cl repulsions.

Full text of DOI:10.1021/acs.joc.8b02780

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Article
Bridge Chlorinated Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acids
Ji#í Kaleta, Igor Ron#evi#, Ivana Cisarova, Martin Dracinsky,
Veronika Šolínová, Vaclav Kasicka, and Josef Michl
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Jan 2019
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Bridge Chlorinated Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acids
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Jiří Kaleta,a,b* Igor Rončević,a Ivana Císařová,c Martin Dračínský,a Veronika Šolínová,a
Václav Kašička,a and Josef Michla,b
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a Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences,
Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
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b Department of Chemistry, University of Colorado, Boulder, CO 80309-0215, United States.
c Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague,
Hlavova 2030, 12840 Prague 2, Czech Republic.
TOC Graphic
ABSTRACT
Radical chlorination of bicyclo[1.1.1]pentane-1,3-dicarboxylic acid is highly selective
and up to four chlorine atoms can be introduced relatively easily without damage to the
strained bicyclic cage.
Combined with hydrodechlorination with TMS3SiH, direct
chlorination provides access to five of the 15 possible chlorinated diacids. Their
configuration has been established by X-ray diffraction. Their pKa values have been
measured by capillary electrophoresis and calculated at the B3LYP-D3BJ/6-311+G(d,p)-
level. The results are in good agreement and reflect the expected trend, from 2.78 ± 0.08 and
4.14 ± 0.10 in the parent to 1.07 ± 0.03 and 2.31 ± 0.03 in the tetrachlorinated diacid). Strain
energy relative to the parent diacid was calculated for all 15 chlorinated diacids and shows a
dramatic increase with successive chlorination, due to non-bonded Cl - Cl repulsions.
INTRODUCTION
The highly strained yet remarkably stable bicyclo[1.1.1]pentane evolved during the
past few decades from a laboratory curiosity to an important player in organic synthesis.1,2,3,4
Hundreds of the relatively easily accessible 1,3- (bridgehead) substituted derivatives have
been described and are essential components of numerous systems, from molecular
devices5,6,7,8,9,10,11,12,13,14,15 to biologically active structures.16,17,18,19,20,21,22,23
Only a few examples of bridge-substituted derivatives are known, almost all of them
either with a halogen or a carbon-based substituent. The introduction of the latter requires a
demanding multistep synthesis of the cage, often from complex precursors.24,25,26 The ease of
halogenation reflects the reactivity of the halogen. Direct iodination and bromination27 do
not take place. Bridge-iodinated derivatives are not known and the only brominated ones are
geminal dibromides, made by addition of dibromocarbene to substituted
bicyclo[1.1.0]butanes.28 Such addition was also used to prepare the first 2,2-dichloro
analogues.28,29,30 It was later discovered that this structure is easily accessible by direct
chlorination of 1,3-disubstitued bicyclo[1.1.1]pentanes, and that subsequent reduction with n-
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Bu3SnH affords the monochlorinated product.27 Direct fluorination under mild reaction
conditions is unselective and yielded 14 of the 15 possible bridge-fluorinated derivatives,
separated by preparative gas chromatography.31 Exhaustive fluorination followed by
repeated crystallization afforded penta- and hexafluoro derivatives in synthetically useful
yields.32
Since there is an obvious need to extend the library of laterally substituted derivatives,
which might also serve as precursors to bridge-bridge bond containing polycyclic cages,33 we
decided to explore the scope of direct chlorination of the parent bicyclo[1.1.1]pentane-1,3-
dicarboxylic acid (0) in the form of its dichloride. We improved the previously published27
syntheses of mono- and dichlorinated diacids and found reaction conditions for three new
diacids with up to four chlorine atoms (Chart 1). Purification requires only simple column
chromatography and all five products are in principle accessible in multigram quantities. We
were unable to introduce five or six chlorine atoms. All five diacids have been fully
characterized, their pKa values measured and compared with calculated numbers, and single-
crystal X-ray structures of four chlorinated dicarboxylic acids and three esters have been
solved. The relative strain energies for all possible chlorinated diacids were calculated.
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Cl
COOH HOOC
Cl
COOH HOOC
Cl Cl
COOH HOOC
HOOC
H
COOH
H
Cl
Cl
Cl
Cl Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
0
1
2a
2x
Cl
Cl
Cl
HOOC
H
COOH HOOC
COOH HOOC
COOH HOOC
COOH
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
Cl
H
H
H
H
H
Cl
Cl Cl
Cl
Cl Cl
H
H
2y
2z
3a
3x
Cl Cl
HOOC
Cl Cl
Cl Cl
HOOC
COOH
HOOC
COOH
H
COOH HOOC
Cl
COOH
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl Cl
Cl Cl
H
H
Cl
Cl
Cl
H
H
H
Cl
Cl
H
Cl Cl
H
H
H
3y
3z
4a
4x
Cl Cl
HOOC
Cl Cl
Cl
Cl Cl
COOH HOOC
COOH HOOC
COOH HOOC
COOH
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl Cl
Cl
H
Cl
Cl Cl
Cl Cl
Cl Cl
Cl Cl
Cl Cl
H
H
Cl Cl
Cl Cl
Cl Cl
H
H
4y
5
4z
6
Chart 1. Chemical structures of parent (0) and chlorinated (1 - 6) diacids.
The labels follow the pattern introduced earlier31 for the fluorinated
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analogues. Previously known and newly synthesized compounds are
highlighted in gray.
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RESULTS
Synthesis. The parent diacid 0 was converted to the dichloride 7 (Scheme 1)34 and
gently chlorinated in CCl4 saturated with Cl2 at 0 - 5 °C under irradiation with visible light to
generate the highly reactive monochlorinated double acid chloride that was immediately
further chlorinated and is related to 8 by methanolysis. Quenching with MeOH afforded 9x
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1
and 10z in a ~7:1 ratio (Scheme 1A), easily separable by column chromatography. H NMR
analysis of the crude reaction mixture revealed only traces of 8. When the chlorination was
performed at 60 - 65 °C, the ratio of products 9x and 10z changed to 1:7 (Scheme 1B).
Subsequent chlorination of the double acid dichloride of 10z leads to formation of 11x, but
under these conditions only traces were detected by 1H NMR in the crude reaction mixture.
Radical chlorination of 7 under harsher reaction conditions employing liquid chlorine
at 50 °C in a high-pressure Schlenk flask followed by methanolysis afforded 11x almost
quantitatively, based on 1H NMR of the crude reaction mixture. It was isolated in 74% yield
by column chromatography (Scheme 1C).
Cl
H3COOC
Cl Cl
H3COOC
Cl Cl
H3COOC
A:
COOCH3
COOCH3
H
COOCH3
H
1. Cl2/CCl4, h
0 - 5 °C
Cl
Cl Cl
Cl
Cl Cl
H
H
+
+
+
+
H
H
H
H
2. CH3OH
Cl
H
10z
, 11%
H
H
H
8
9x
, traces
, 76%
Cl Cl
H3COOC
Cl Cl
H3COOC
B:
R
OC
R
CO
COOCH3
H
COOCH3
H
H3COOC
COOCH3
Cl
Cl
Cl
1. Cl2/CCl4, h
60 - 65 °C
Cl
Cl
Cl Cl
0 R
:
= OH
= Cl
SOCl2
reflux
97%
Cl Cl
H
H
7 R
:
Cl
Cl
Cl Cl
11x, traces
H
H
2. CH3OH
Cl
H
10z
, 63%
H
9x
H
, 7%
C:
H3COOC
COOCH3
Cl
Cl
1. Cl2 (liq.)/CCl4
Cl
Cl
H
h
50 °C
H
Cl
Cl
Cl Cl
11x
2. CH3OH
, 74%
Scheme 1. Radical chlorination of 0.
Reduction of 9x with TMS3SiH in refluxing benzene in the presence of AIBN
provided 8 in nearly quantitative yield (Scheme 2).20 Under the same reaction conditions
10z gave 9a quantitatively and in excellent isolated yield. The other dichlorinated isomer
was not detected. Surprisingly, the reduction of 11x led to complete destruction of the cage
and only traces of 10z were observed in the 1H NMR spectrum of the crude reaction mixture
(Scheme 2).
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Cl Cl
H3COOC
Cl
TMS3SiH
AIBN
COOCH3
H3COOC
COOCH3
Cl Cl
Cl
H
H
Benzene
80 °C
H
H
H
H
H
H
H
9x
8
, 94%
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Cl Cl
H3COOC
Cl
H3COOC
TMS3SiH
AIBN
COOCH3
COOCH3
Cl
Cl Cl
Cl
Cl
Benzene
80 °C
H
H
H
H
H
H
Cl
10z
Cl
H
9a
, 86%
H3COOC
COOCH3
Cl
TMS3SiH
AIBN
Cl
Products of
decomposition
Cl
10z
traces
Cl
+
Benzene
80 °C
H
H
Cl
Cl
Cl Cl
11x
Scheme 2. Reduction using TMS3SiH.
Carboxylic acids 1, 2a, 2x, 3z, and 4x were liberated from the corresponding methyl
esters 8, 9a, 9x, 10z, and 11x with LiOH in aqueous THF (Scheme 3) and the products were
isolated in 87 - 97% yields.
1. LiOH.H2O
Cl1-4
COOCH3
Cl1-4
COOH
2. HCl/H2O
H3COOC
HOOC
THF
H2O
8
9a
9x
1
, 87%
25 °C
2a
, 91%
2x
, 97%
3z
, 92%
4x
, 88%
10z
11x
Scheme 3. Liberation of carboxylic acids 1, 2a, 2x,
3z, and 4x from methyl esters.
In contrast, basic hydrolysis of 9x under heterogenous conditions gave not only the
expected 2x but also the cyclobutene derivative 12 (Scheme 4), which was characterized as
the diester 13 after quantitative esterification with ethereal diazomethane (Scheme 4).
Cl
Cl Cl
OOC
R
COO
Cl
R
R
COO
HO
R
COO
OH-
OH-
Cl-
+
-
1. NaOH
2. HCl/H2O
Cl Cl
HOOC
Cl Cl
H3COOC
Cl
HO
R
COO
COOH
COOCH3
+
H2O
50 °C
R
COO
= H, 18%
9x
2x
, 55%
12 R
:
CH2N2
Et2O
13 R
:
= CH3, 100%
25 °C
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Scheme 4. Heterogeneous basic hydrolysis of 9x and proposed formation
mechanism of a cyclobutene.
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X-ray Crystallography. We were able to grow high quality single crystals of four
diacids 1, 2x, 3z and 4x from acetone. Compound 2a crystallized from the same solvent as
well, but the crystals decomposed at a low temperature. High temperature data provided a
highly disordered structure whose satisfactory solution could not be reached. Crystals of the
esters 9a, 9x, and 10z were obtained by slow crystallization from CH2Cl2. Compound 8 is an
oil at ambient conditions. All attempts to grow single crystals of 11x failed, because it
usually remained oily and slowly solidified once solvents evaporated, or formed an emulsion
during diffusion experiments. The crystallographic parameters are summarized in Table S1
in the Supporting Information. Almost all the compounds formed monoclinic crystals and
only the crystals of 3z and 9a were triclinic.
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The X-ray diffraction data established the positions of the Cl atoms unambiguously.
Figure 1 shows ORTEP visualizations of selected chlorinated representatives: acids 1, 2x, 3z,
and 4x, and ester 9a. The chlorine atoms were in all cases located in the plane defined by the
three methylene carbons.
Figure 1. ORTEP visualizations of carboxylic
acids 1, 2x, 3z, and 4x and ester 9a, representative
of all available isomers of chlorinated
bicyclo[1.1.1]pentane cages.
Atom labeling:
chlorine = green, oxygen = red, carbon = gray, and
hydrogen = white. Thermal ellipsoids are shown
with 50% probability.
Selected interatomic distances are presented in Table 1 (Figure 2). The length of
skeletal C-C bonds connecting the bridgehead C atoms with those of the chlorinated
methylene bridges is almost constant in the relatively narrow region 154.2 - 155.9 pm. The
C-C bonds connecting the bridgehead atoms with CH2 bridge carbon atoms exhibit a clear
trend. Every attached chlorine atom causes a slight elongation of this bond, from the original
155.3 pm in 1 to 157.4 pm in 4x. The length of the exocyclic C1-C6 and C3-C7 bonds is
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almost constant at 149.1-150.1 pm. In contrast, the inter-bridgehead distance C1•••C3
increases with the number of Cl atoms attached to the bicyclic skeleton, from 187.1 ppm in 1
to 190.3 ppm in 4x. Thus, each additional chlorine atom attached to the cage increases the
inter-bridgehead distance by ~1.1 pm. As expected, the C=O bonds are slightly shorter in
methyl esters (119.5 - 120.5 pm) than in carboxylic acids (121.2 - 124.5 pm). The opposite
trend is observed for C-OR bonds, which are shorter in carboxylic acids (125.7 - 130.9 pm)
and longer in esters (131.7 - 132.9 pm). The C-Cl bonds are 175.5 - 178.2 pm long. A trend
in the length of the C-Cl bonds was found in 4x: C1-Cl1 and C2-Cl4 are significantly longer
(177.8 - 178.2 ppm) than C1-Cl2 and C2-Cl3 (175.5 - 175.7 pm).
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The geometrical parameters derived from the positions of disordered atoms of 3z were
excluded from consideration.
Table 1. Observed Interatomic Distances (pm) in Chlorinated Bicyclo[1.1.1]pentane-
1,3-dicarboxylic Acids and Methyl Esters.
1
2x
3za
(X1 = X2
= X4 = Cl,
X3 = X5 =
X6 = R =
H)
4x
9a
(X1 = X3
= Cl, X2 =
X4 - X6 =
H, R =
CH3)
9x
10z
(X1 = X2
= X4 = Cl,
X3 = X5 =
X6 = H, R
= CH3)
155.7
(X1 = X2
= Cl, X3 -
X6 = R =
H)
(X1 - X4 =
Cl, X5 =
X6 = R =
H)
(X1 = X2
= Cl, X3 -
X6 = H, R
= CH3)
(X1 = Cl,
X2 - X6 =
R = H)
C1-C2
C1-C4
C1-C5
C3-C2
C3-C4
C3-C5
C1-C6
C3-C7
C6=O1
C6-O2R
C7=O3
C7-O4R
C2-X1
C2-X2
C4-X3
C4-X4
C5-X5
155.9
155.8
155.3
154.9
154.6
155.6
149.1
149.3
122.7
130.3
122.4
129.3
176.4
154.2
156.0
156.7
155.3
156.5
155.1
149.3
149.3
121.7
130.9
124.5
127.4
176.6
177.9
147.0
160.2
162.0
146.6
159.4
160.9
149.6
149.6
121.2
129.5
121.2
129.5
155.8
155.9
157.4
156.0
155.4
158.0
149.6
149.3
124.0
125.7
124.2
126.0
177.8
175.5
175.7
178.2
154.5
155.4
156.6
155.0
156.1
155.3
149.2
149.2
120.3
132.4
120.5
132.9
155.5
155.9
155.8
155.4
155.7
156.6
149.6
149.5
119.8
132.6
119.5
132.0
177.2
177.9
154.6
155.9
155.4
156.1
156.3
150.1
150.1
119.6
131.7
120.0
132.2
176.6
178.4
178.1
b
b
-
178.1
-
177.2
b
b
b
b
b
-
-
-
178.3
-
-
b
b
b
b
-
-
159.4c
-
-
176.6
b
b
b
b
b
b
b
-
-
-
-
-
-
-
b
b
b
b
b
b
b
C5-X6
-
-
-
-
-
-
-
C1•••C3
C2•••C4
C2•••C5
C4•••C5
187.1
211.9
218.1
214.4
188.2
215.2
214.4
214.6
189.0
212.4
213.4
218.2
190.3
219.0
212.9
212.7
189.2
213.3
217.2
210.6
188.9
215.2
213.9
214.9
189.5
210.7
213.8
217.1
a Interatomic distances are inaccurate due to crystal disorder. b The C-H distance on the BCP
c
cage was set at 100.0 pm. The bond appears to be anomalously short due to high crystal
disorder.
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Figure 2. Labels for interatomic distances used in
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Table 2.
Computed Geometries of Bridge Chlorinated Bicyclo[1.1.1]pentanes. Geometries
of all possible bridge chlorinated carboxylic acids were calculated with density functional
theory (DFT) in the gas phase, and selected interatomic distances are collected in Table S2
(Supporting Information). Known compounds are highlighted in gray.
The computed interatomic distances reproduce the experimental trends. Substitution
of hydrogen atoms on methylene bridges causes an increase of the interbridgehead distance
from 186.8 pm in 0 to 193.3 pm in 6; for each additional chlorine atom in the cage the
interbridgehead distance increases by ~1.1 pm. This trend is observed both in measured and
calculated C-Cl bond lengths in 4x. The C-Cl bonds in 6 are longer than average.
Computed Strain Energy. The strain increase in compounds 1 - 6 relative to 0 was
calculated using the hypothetical reaction shown in Scheme 5, where n and m are the
numbers of C atoms carrying one and two chlorine atoms, respectively.
Cl Cl
H
H
H
H
(H)
(H)
Cl Cl
Cl
H
H H
+
n
+
m
+ (n + m)
Cl
Cl
H
H
(H)
(H)
Cl Cl
(H)
(H)
0
C3H6Cl2
C3H7Cl
1
6
C3H8
-
Scheme 5. Hyperhomodesmotic reactions for the estimation of strain energies.
For example, the strain for diacid 5, which has five chlorine atoms, was calculated
using Equation 1.
0 + 2 × C3H6Cl2 + C3H7Cl → 5 + 3 × C3H8
(1)
The process conserves both the number of carbon-carbon bond types and the number
of each type of carbon atoms (sp3, sp2, sp) and satisfies the criteria for hyperhomodesmotic
reactions.35 Calculated relative strain energies for all possible chlorinated derivatives of 0 are
presented in Table 2.
Table 2.
Calculated Relative Strain Energies (kcal/mol) in Chlorinated
Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acids.a
Strain energy
Cmpd.
Strain energy
(kcalmol1)
17.63
Cmpd.
(kcalmol1)
0
1
2a
2x
2y
2z
0
3y
3z
4a
4x
4y
4z
2.46
6.25
6.56
7.22
11.11
12.14
24.90
26.32
25.13
30.69
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3a
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12.84
16.43
5
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43.68
74.15
a Known compounds are highlighted in gray.
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The calculated strain does not grow evenly as hydrogen atoms are gradually
substituted by chlorines. Combinations of substituents that place H and Cl, and even more
so, Cl and Cl, into syn contact cause additional strain. Up to the tetrachlorinated diacids, the
steric crowding that results from these syn contacts can be partially alleviated by distortion of
the threefold symmetry about the bridgehead-bridgehead axis and strain energies are very
approximately additive. They can be estimated to within a few kcal/mol by assigning about 3
kcal/mol of strain to each syn H,Cl contact and about 15 kcal/mol of strain to each syn Cl,Cl
contact. In penta- and hexachlorinated diacids, relief of strain by this type of angular
distortion is no longer available, and the strain introduced by the two or three Cl,Cl syn
contacts is disproportionately high, 43.68 kcal/mol in 5 and 74.15 kcal/mol in 6.
The effect of syn contacts can be illustrated by examples. Three of the dichlorinated
diacids, 2a, 2x, and 2y, have two syn H,Cl contacts each, and have similar relative strain
energies (6.25 - 7.22 kcal/mol), but the fourth one 2z, with one syn Cl,Cl contact, has almost
twice as much strain (11.11 kcal/mol). Similarly, two of the trichlorinated diacids (3a and
3z) have three syn H,Cl contacts but no Cl,Cl contacts and are significantly less strained
(12.14 and 12.84 kcal/mol) than the other two structures (3x and 3y) that have one H,Cl and
one Cl,Cl syn contact, with strain energies 16.43 and 17.63 kcal/mol, respectively. Diacid 4z,
with two Cl,Cl syn contacts, is more strained (30.69 kcal/mol) than the isomers 4a, 4x, and
4y, which have only one Cl,Cl and two H,Cl syn contacts, and whose strain lies between
24.90 and 26.32 kcal/mol.
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Due to the hyperhomodesmotic scheme used, the relative strain energies do not
correspond to relative energies (i.e., stabilities). The most important difference is that
geminal dichlorides are less stable than their vicinal isomers (Table S3 in Supporting
Information). For example, the strain energies of 2a and 2y are virtually identical, but the
geminal 2x is about 5 kcal/mol less stable than the vicinal 2a.
Computed Radical Abstraction Paths. In these computations, zero-point vibration
energies were included.
(i) Chlorination. Halogenation of 2x starts with hydrogen abstraction performed by a
chlorine radical approaching the methylene bridge either from the syn or anti side relative to
the CCl2 bridge (Scheme 6). The CHCl units are nearly linear in both cases. The transition
state for the anti approach is 0.7 kcal/mol lower in energy than that for the syn approach and
results in the more stable radical 2x•anti (4.3 vs. 4.9 kcal/mol for 2x•syn). The
interconversion of 2x•syn to 2x•anti involves a barrier of 0.8 kcal/mol. Their further
barrierless chlorination can lead to 3y and 3z, respectively.
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8
H
Cl2
HCl
Cl
Cl
H
H
Cl2
HCl
TS
Cl2
HCl
(5.68)
H
9
Cl
Cl
H
H
10
11
12
13
14
15
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H
Cl
Cl
H
Cl2
2xsyn
H
Cl2
Cl
H
2xanti
H
(4.85)
Cl
H
Cl
Cl
H
(4.27)
H
H
Cl
H
Cl2
Cl
TSsyn
Cl
H
(2.72)
TSanti
H
H
(2.02)
Cl
Cl
2x
(0.00)
H
HCl
Cl
H
Cl
Cl
Cl
3y
(-26.95)
H
HCl
Cl
H
H
Cl
H
H
Cl
Cl
3z
(-30.13)
H
Scheme 6. Formation of 3y and 3z from 2x.
Further chlorination of 3y and 3z occurs in similar manner (Scheme 7). The CHCl
units in both transition states are linear again. Surprisingly, the barriers are different. The
formation of 3z• proceeds with a barrier of 3.3 kcal/mol, while the 3y• is formed without any
barrier. The energies of 3y• and 3z• differ by 1 kcal/mol in favor of the latter, but their
interconversion involves a relatively high barrier of 5.8 kcal/mol.
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Cl
Cl2
HCl
Cl
H
Cl
H
TS
Cl2
Cl2
Cl
(5.76)
Cl
H
Cl
Cl
Cl
H
Cl2
10
11
12
13
14
15
16
17
18
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Cl
H
H
Cl2
HCl
Cl
TS
H
Cl
Cl
3y
(3.17)
H
H
Cl
Cl
Cl
Cl
Cl2
HCl
H
(3.32)
H
Cl
H
TS
(2.
09)
Cl
H
Cl
Cl2
Cl
3y
Cl
H
(1.79)
Cl
H
Cl
H
3z
(0.80)
Cl
H
Cl
H
3z
(0.00)
HCl
Cl
Cl Cl
Cl
H
Cl
H
4x
(-17.85)
Scheme 7. Possible formation of 4x from 3z and 3y.
(ii) Hydrodechlorination. Scheme 8 presents the energies of the pyramidalized
radicals potentially involved in the hydrodechlorination of 3z and the activation energies of
their interconversion. The stereoisomer 2a• is ~1.5 kcal/mol more stable than 2y•. In the
transition structures for chlorine atom abstraction the CClSi unit is close to linear, and the
activation energies for the formation of 2a• and 2y• are very close to zero. The conversion of
2a• into 2y• involves a barrier of ~8 kcal/mol. The CHSi units in the transition structures for
hydrogen transfer are also nearly linear and both activation energies are again negligible.
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HSi(TMS)3
Si(TMS)3
(TMS)3SiH
(TMS)3Si
(TMS)3SiH
(TMS)3Si
HSi(TMS)3
Si(TMS)3
Cl
Cl
Cl
Cl
Cl
Cl
H
H
Cl
Cl
H
H
Cl
H
H
H
H
H
Cl
H
TSsyn
(TMS)3SiH
(TMS)3SiCl
Cl
H
TSanti
Cl
H
10
11
12
13
14
15
16
17
18
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(17.79)
3z Si
+
(17.39)
anti
3z Si
+
syn
Cl
(16.92)
(15.79)
H
H
Cl
TS
H
(TMS)3SiH
(TMS)3SiCl
(TMS)3SiH
(TMS)3SiCl
(7.70)
ClSi(TMS)3
Si(TMS)3
Cl
ClSi(TMS)3
Si(TMS)3
H
H
Cl
Cl
H
(TMS)3SiCl
(TMS)3Si
H
H
H
(TMS)3SiCl
(TMS)3Si
Cl
H
2y
(1.47)
Cl
H
Cl
H
H
2a
(0.00)
ClSi(TMS)3
Si(TMS)3
H
H
H
Cl
H
(TMS)3SiCl
(TMS)3Si
H
Cl
Cl
Cl
TS
H
H
H
(-6.34)
H
H
2y SiH
+
Cl
H
Cl
TS
H
Cl
H
H
Cl
H
(-6.51)
H
H
H
H
2a SiH
+
Cl
2y
H
(-7.37)
Cl
2a
(-7.51)
(-20.11)
(-21.29)
Scheme 8. Dehydrochlorination of dimethyl ester of 3z.
Acidity Constants (pKa). The pKa values were measured in water solutions by
capillary electrophoresis (CE). The mixed acidity constants, pKamix, related to the activity of
hydroxonium cations at 25 mM ionic strength, and the ionic mobilities μ1- and μ2- of the
mono- and divalent anions of the diacids 0, 1, 2a, 2x, 3y, and 4y, were determined by
nonlinear regression analysis of the pH dependence of their effective mobilities measured in a
series of background electrolytes within a pH range of 0.92 - 5.51 at constant ionic strength
(25 mM) and temperature (25 °C). These pKamix values were converted to the
thermodynamic acidity constants pKath using the Debye-Hückel theory.36 The mixed and
thermodynamic pKa values and ionic mobilities are summarized in Table 3.
Table 3. Acidity Constants pKa of 0, 1, 2a, 2x, 3z, and 4x at 25 C.a
μ2-
1-
th
th
mix
mix
Cmpd.
0b
pKa,1
pKa,2
pKa,1
pKa,2
(10-9m2V-1s-1)
(10-9m2V-1s-1)
2.78 ± 0.08
2.24 ± 0.07
1.82 ± 0.05
1.86 ± 0.05
1.43 ± 0.03
1.07 ± 0.03
4.14 ± 0.10
3.49 ± 0.09
2.90 ± 0.07
3.05 ± 0.07
2.57 ± 0.04
2.31 ± 0.03
2.71 ± 0.08
2.17 ± 0.07
1.75 ± 0.05
1.79 ± 0.05
1.36 ± 0.03
1.00 ± 0.03
3.94 ± 0.10
3.28 ± 0.09
2.69 ± 0.07
2.84 ± 0.07
2.36 ± 0.04
2.10 ± 0.03
-19.0 ± 0.0
-19.0 ± 0.0
-19.0 ± 0.0
-19.0 ± 0.0
-19.0 ± 0.0
-19.0 ± 0.0
-37.9 ± 0.9
-38.2 ± 0.7
-38.0 ± 0.5
-37.8 ± 0.5
-37.1 ± 0.3
-37.5 ± 0.2
1
2a
2x
3z
4x
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a pKath: thermodynamic acid dissociation constant (at zero ionic strength), pKamix: mixed acid
dissociation constant at ionic strength 25 mM, μ1- and μ2-: ionic mobilities of the univalent
b
and divalent anionic forms of the analyzed acids. Previously published values obtained by
potentiometric titration: pKa,1 = 3.22 ± 0.02, pKa,2 = 4.26 ± 0.03.32
7
8
9
In order to estimate the acidity of 5 and 6, the B3LYP-D3/6-311+G(d,p) results
obtained using the cluster-continuum model (two explicit molecules of water plus SMD)
were compared with measured pKa values of 0, 1, 2a, 2x, 3y, and 4y (Table 3). A good linear
correlation (R2 = 0.91, Figure S4 in Supporting Information) was found between the
calculated reaction energies and the measured acidities, producing a mean unsigned error of
0.22 for predicted pKa values, shown in Table 4. The errors of the predicted values appear to
be uniformly distributed (plot of residuals in Supporting Information), suggesting that the
predictions for 5 and 6 should be within the same error margins as 0, 1, 2a, 2x, 3y, and 4y.
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Table 4. Predicted pKa Values for Compounds 0, 1, 2a, 2x, 3y, 4y, 5, and 6 with Absolute
Deviations from Measured Values.
Cmpd. pKa,1 Error pKa,2 Error
0
1
3.16 0.38 4.07 0.07
2.66 0.42 3.27 0.22
1.90 0.08 2.73 0.17
2.17 0.31 2.84 0.21
1.59 0.16 2.35 0.22
2a
2x
3y
4y
5
0.97
0.64
0.28
0.1
-
-
1.97 0.34
1.27
0.77
-
-
6
1
NMR Spectroscopy. Results obtained from H, 13C, 13C APT (Attached Proton
Test), HSQC (Heteronuclear Single Quantum Coherence) and HMBC (Heteronuclear
Multiple Bond Correlation) spectra of 0, 1, 2a, 2x, 3y, and 4y are collected in Figure 3. The
4
proton NMR spectrum of 2x exhibits a complex AA'BB' pattern and the geminal and J
coupling constants were therefore extracted from 13C satellites. To confirm the assignment of
the signals and couplings further, we compared the experimental data with those calculated
by DFT. The agreement is very good (Figures S5 and S6 in Supporting Information).
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Figure 3. Proton (blue) and carbon (black) NMR chemical shifts for 0, 1, 2a, 2x, 3z, and 4x
measured in acetone-d6 at 25 °C. Proton-proton coupling constants are shown in red.
DISCUSSION
Chlorination of Methylene Bridges. Unlike fluorination, the chlorination of
bicyclo[1.1.1]pentane1,3-dicarboxylates in the form of their dichlorides is fairly selective and
favors the formation of certain isomers, while others are inaccessible. The abstraction of the
first hydrogen atom from one of the CH2 bridges is relatively difficult, but the presence of the
first chlorine atom on a CHCl bridge dramatically increases the rate of abstraction of the
second hydrogen (Scheme 1A). This is attributable to the radical stabilizing effect of the first
chlorine.27 As a result, the yield of the monochlorinated product is poor and the only directly
dichlorinated diacid that results in useful yield after methanolysis and hydrolysis is the
geminal 2x. The isomers 2a, 2y, and 2z are not accessible by direct chlorination.
Subsequent chlorination of the dichloride of the geminally dichlorinated diacid 2x
(Scheme 1B) starts with the abstraction of a hydrogen atom from one of the remaining two
CH2 bridges. The resulting bridge radical is surrounded by a bulky CCl2 bridge on one side
and a much smaller CH2 bridge on the other. It abstracts a chlorine atom from Cl2 more
readily at the face that is adjacent to the CH2 and not the CCl2 bridge, probably not only
because this face is less hindered, but also because at the transition state there is a sigma-
conjugated W-shaped path to one of the geminal chlorine atoms.37 Attack at this face
ultimately produces the trichlorinated diacid 3z to the exclusion of the isomer 3y, which
would require an attack at the face adjacent to the CCl2 bridge (Scheme 6).
The dichloride of the trichlorinated diacid 3z has two bridges that could be further
chlorinated, CHCl and CH2. Activation by the already present chlorine atom overcomes the
effect of steric hindrance and abstraction of the next hydrogen atom occurs exclusively on the
more hindered CHCl bridge (Scheme 7). The need to overcome steric problems undoubtedly
is the reason why much harsher reaction conditions are required. The doubly geminal 4x is
thus the only tetrachlorinated diacid that results after workup of the reaction mixture (Scheme
1C), in spite of its 26.32 kcal/mol calculated strain associated with the steric repulsion in its
syn Cl,Cl contact. The strain is comparable with that in the previously published penta- and
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hexafluorinated bicyclo[1.1.1]pentane-1,3-dicarboxylic acid analogs (21.8 and 32.9 kcal/mol,
respectively).30 The slightly less strained tetrachlorinated diacids that would result from
substitution of hydrogen atoms on the CH2 bridge (4y, 25.13 kcal/mol, and 4a, 24.90
kcal/mol) are not formed.
7
The highly strained 4x seems to be surprisingly stable and even extended chlorination
of its dichloride did not cause any degradation of its bicyclic cage. A thorough examination
of the reaction mixture by H NMR and MS revealed a trace of a compound that could be
8
9
1
10
11
12
13
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59
60
assigned as a double methyl ester of a pentachlorinated diacid, but it was not isolated and its
structure remains unproven. Calculations suggest that the introduction of a fifth chlorine
atom to the bicyclic cage will increase the relative strain energy by an additional ~20
kcal/mol, to 43.68 kcal/mol in 5. Substitution of the last hydrogen atom in 5 by chlorine
should lead to perchlorinated 6, whose enormous calculated strain (74.15 kcal/mol) would
exceed the strain of the bicyclic cage itself (68 kcal/mol38), and would be only slightly lower
than the standard strength of the C-Cl (81 - 84 kcal/mol) and C-C (83 - 85 kcal/mol) bonds.39
Reduction of Chlorinated Cages. Reduction of the polychlorinated diesters with
TMS3SiH opens a synthetic path to isomers that are not accessible by direct chlorination. We
have revised the previously published related procedures20,27 and were able to significantly
increase isolated yields by careful control of reaction conditions. Monitoring of the progress
of the reaction allowed us to draw the following conclusions: (i) the reduction of 9x and 10z
to 8 and 9a, respectively, is a clean and quantitative process, but imperfect product isolation
reduces the yields slightly, (ii) reactions performed in benzene-d6 do not lead to incorporation
of deuterium into the final products.
The reduction of 9x that affords monochlorinated 8 in high isolated yield was
published before27 and does not require any additional comment. In contrast, an explanation
is needed for the perfect specificity with which the reduction of the trichlorinated double
methyl ester 10z of the diacid 3z leads solely to the dichlorinated double ester 9a derived
from the diacid 2a and none of the also expected dichlorinated double ester derived from the
diacid 2y, which is only 1 kcal/mol more strained (7.22 kcal/mol vs. 6.25 kcal/mol, Table 2).
Similar trends were noticed previously in the fluorinated analogues.31
There is little doubt that the reaction of 10z is initiated by the abstraction of one of the
geminal chlorine atoms by the tris(trimethylsilyl)silyl radical to yield a chlorine-stabilized
bridge radical, and the question that needs to be answered is why this radical abstracts a
hydrogen from tris(trimethylsilyl)silane at the face adjacent to the CH2 bridge and not the
face adjacent to the CHCl bridge (Scheme 8). The calculations do not provide a reliable
argument for differentiating the rates of formation of 2a• and 2y•, but they provide their
relative stabilities. If their interconversion is fast enough to establish an equilibrium, the ratio
of their concentrations is of the order of 8:1 at 80 C, and if the rates of hydrogen abstraction
by these two radicals are similar, the expected ratio of 2a and 2y will also be 8:1. Then, the
actually observed product 2a is indeed predicted to be dominant, but not as exclusively as is
observed.
It is interesting to ask why 2a• is more stable than 2y•. Steric conditions appear to be
similar at both faces, but stereoelectronic conditions are different. Only abstraction at the
CH2 bridge face offers a W-shaped sigma-conjugation path for donation of electron density
from the electropositive Si atom of the silane to the electronegative Cl atom on the CHCl
bridge, stabilizing the hydrogen abstraction transition state, while abstraction at the CHCl
bridge offers a destabilizing W-shaped interaction path between two C-Cl bonds.37
An attempt to reduce 11x under the same conditions led to a complete destruction of
the bicyclic cage and only traces of 10z were detected in the crude reaction mixture (Scheme
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9). The reaction was fast and the starting 11x was completely consumed in less than 30 min,
although the same kind of reduction performed on 9x or 10z required more than 10 hours for
completion. It is likely that strain relief promotes the abstraction of chlorine atom.
The radical that results from the abstraction of a chlorine atom from 11x by a silyl
radical has nominally the same cage as that produced by the abstraction of a hydrogen atom
from 3z by a chlorine atom. Yet, the final products of the two reactions are very different.
The former leads to a breakdown of the bicyclic cage, whereas the latter produces an almost
quantitative yield of 4x. Two factors come to mind as a possible explanation, and both could
play a role. (i) The difference in the reaction products could be due to the difference of the
concentrations of the reaction partners in the two cases. The conversion of 3z to 4z occurs in
liquid chlorine, undoubtedly giving the intermediate radical very little time to rearrange and
lose its cage structure, whereas the abstraction of a Cl atom from 11x occurs in a relatively
dilute solution in benzene, with a much longer time during which this rearrangement can
occur. (ii) The radicals formed in the two abstraction reactions could only nominally have
identical cages and in reality could differ in the sense of pyramidalization. If their
interconversion is slow on the reaction time scale, each can give different products. This is
illustrated in Schemes 6 and 8, assuming that the abstraction of hydrogen and chlorine occurs
with retention of configuration. This issue deserves closer attention but lies outside the scope
of the present paper.
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Cl Cl
Cl
H
Cl
H
Cl
Cl
Cl
-
-
4x
Cl Cl
Cl Cl
H
H
Cl
H
H
Cl Cl
cage opening
products
H
H
Cl
H
3z
Scheme
9.
Attempted
hydrodechlorination of 4x.
Structure of the Chlorinated Cages. The changes in structural parameters that
describe the bicyclic cage as the number of chlorine substituents increases are relatively
minor and can be understood simply. Thus, Bent's rules account for the increase in the CCC
valence angle at bridge carbons with increasing number of chlorine substituents, which
causes an increase in the inter-bridgehead distance. The calculated increase in the C-Cl bond
lengths in 6 can be understood as a result of non-bonded Cl - Cl repulsions.
Saponification of Methyl Esters. Basic hydrolysis of 8, 9a, 9x, 10z, and 11x
performed under homogenous reaction conditions (LiOH in a THF/water mixture) proceeds
as expected and yields salts of the acids 1, 2a, 2x, 3z, and 4x in nearly quantitative yields. In
contrast, heterogenous hydrolysis of 9x with aqueous NaOH at a slightly elevated
temperature of 50 °C afforded after workup in addition to 2x also an unexpected cyclobutene
derivative 12 that was characterized as the methyl ester 13 (Scheme 4). We did not examine
this transformation in detail, but propose a possible mechanism for the observed outcome.
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The cage opening starts with an unprecedented attack by hydroxide anion at one of the
methylene bridges in 9x, which leads to C-C bond breaking and stabilization of the negative
charge by conjugation with the COOR group. Subsequent elimination of a chloride anion
produces the cyclobutene ring.
7
Acidity Constants in Water. The acidity of parent 0 (pKa,1 = 2.78 ± 0.08, pKa,2
=
8
9
4.14 ± 0.10) determined by capillary electrophoresis is higher than the previously
published32 values obtained by potentiometric titration (pKa,1 = 3.22 ± 0.02, pKa,2 = 4.26 ±
0.03). Acidity is increased by chlorine substitution on the methylene bridges in an almost
additive manner: pKa,1 drops by about half a pH unit upon each Cl for H replacement, and
pKa,2 drops slightly more. This can be compared with the effect of a single chlorine atom in
the β position of propionic acid, which lowers the pKa value by 0.77 pK units.40 The four
chlorine atoms in 4x increase each of the acidities by 1.7 - 1.8 pH units, and the acidities of
the isomeric dichlorinated acids 2a and 2x are nearly identical (Table 3).
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The calculated pKa values of 0, 1, 2a, 2x, 3z, and 4x correlate reasonably well with
the measured numbers and this allows us to predict the acidities of 5 and 6. The introduction
of the fifth chlorine atom in 5 lowers both pKa values, to 0.64 and 1.27. The hexachlorinated
diacid 6 follows the same trend to the exceptionally low computed values of pKa,1 = 0.28 and
pKa,2 = 0.77. This diacid should be even more acidic than the corresponding perfluorinated
analogue (pKa,1 = 0.73 and pKa,2 = 1.34).32
13
Nuclear Magnetic Resonance Spectroscopy. Comparison of C NMR chemical
shifts of chlorinated diacids 1, 2a, 2x, 3z, and 4x with the parent diacid 0 allow us to draw the
following conclusions: (i) resonances of CH2 bridges in 1, 2a, 2x, 3z, and 4x usually appear
at 44.2 - 49.7 ppm, slightly above that in 0 (53.0 ppm). (ii) Substitution of one hydrogen
atom by chlorine on a CH2 bridge shifts its carbon resonance ~16 ppm downfield and signals
of CHCl units are found at 66.8 - 71.4 ppm. (iii) Replacement of the second hydrogen shifts
the signal by an additional ~21 ppm downfield and signals of CCl2 units appear at 87.5 - 92.7
ppm. (iv) Resonances of the bridgehead carbons are sensitive to chlorine substitution at the
bridges: 38.1 ppm in 0 and 65.4 ppm in 4x. Each chlorine atom on a bridge shifts the
resonance of the bridgehead carbon atoms ~7 ppm downfield. (v) An opposite but weaker
trend is observed for chemical shifts of carboxylic carbon atoms: each chlorine atom on a
methylene bridge shifts them upfield by ~2.2 ppm, from 170.6 ppm in 0 to 161.7 ppm in 4x.
SUMMARY
Three new bridge-chlorinated bicyclo[1.1.1]pentane derivatives were synthesized and
their preferential formation was rationalized. The remarkable stereoselectivity in both the
introduction and the removal of chlorine atoms can be understood in terms of steric and
stereoelectronic effects (sigma conjugation). All five known bridge-chlorinated cages were
analyzed by X-ray diffraction and the results showed that each chlorine atom attached to the
cage increases the inter-bridgehead separation. Acidities of the dicarboxylic acids were
determined both by capillary electrophoresis and computationally and the results were in
good agreement. Substitution of each hydrogen atom by chlorine decreases both pKa values.
EXPERIMENTAL SECTION
Materials. All reactions were carried out under argon atmosphere with dry solvents
freshly distilled under anhydrous conditions, unless otherwise noted. Standard Schlenk and
vacuum line techniques were employed for all manipulations of air- or moisture-sensitive
compounds. Yields refer to isolated, chromatographically and spectroscopically homogenous
materials, unless otherwise stated.
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Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (0) was synthesized according to a
published procedure.34 THF and ether were dried over sodium with benzophenone and
distilled under argon prior to use. Benzene-d6 was dried over sodium and distilled under
argon prior to use. Carbon tetrachloride was dried over CaH2 and distilled under argon prior
to use. All other reagents were used as supplied unless otherwise stated.
Procedures. Analytical thin-layer chromatography (TLC) was performed using
precoated TLC aluminum sheets (Silica gel 60 F254). TLC spots were visualized using either
UV light (254 nm) or a 5% solution of phosphomolybdic acid in ethanol, and heat (400 °C)
as a developing agent. Flash chromatography was performed using silica gel (high purity
grade, pore size 60 Å, 70 - 230 mesh). Melting points are reported uncorrected. Infrared
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spectra (IR) were recorded in KBr pellets. Chemical shifts in H and C NMR spectra are
1
reported in ppm on the δ scale relative to CHCl3 (δ = 7.26 ppm for H NMR and δ = 77.0
13
1
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ppm for C NMR) and acetone-d6 (δ = 2.05 ppm for H NMR and δ = 29.8 ppm for C
NMR) as internal references. Splitting patterns are assigned as s = singlet, d = doublet, t =
triplet, m = multiplet, br = broad signal.
High-resolution mass spectra (HRMS) using atmospheric-pressure chemical
ionization (APCI) and electrospray ionization (ESI) were obtained on a mass analyzer
combining linear ion trap and the Orbitrap, and those using chemical ionization (CI) mode
were taken on a time-of-flight mass spectrometer.
X-ray Diffraction. Crystallographic data were collected on Bruker D8 VENTURE
Kappa Duo PHOTON100 by IμS micro-focus sealed tube either with MoKα radiation (λ =
0.71073 Å) 1, 2x, 4x, and 9x or CuKα radiation (λ = 1.54178 Å) 2a, 9a, and 10z. The
measurements were performed at 150 K, except for 4x, which was measured at 200 K,
because of a phase transition at a lower temperature. The structures were solved by direct
methods (XT)41 and refined by full matrix least squares based on F2 (SHELXL2014).42 The
hydrogen atoms on carbon atoms were fixed into idealized positions (riding model) and
assigned temperature factors of either Hiso(H) = 1.2 Ueq(pivot atom) or Hiso(H) = 1.5 Ueq
(pivot atom) for methyl moiety. The hydroxyl hydrogens were found on difference electron
density map and refined as riding on the corresponding oxygen atom.
The molecules of carboxylic acids in the study are prone to disorder in their crystal
structures, mostly by rotation or mirroring of the bicyclic cage. The ruling contacts in their
crystals assembly are doubled short hydrogen bonds C=O•••H-O-C of carboxylic moieties
forming infinite chains.
In 1 three equatorial carbon atoms of bicyclo[1.1.1]pentane are disordered over two
locations, whereas the chlorine atom keeps its place.
The diacid 3z is disordered in a more complicated manner. The equatorial carbon
atoms are again disordered in two positions, each along operation of inversion of the space
group. Three chlorine atoms are distributed in four positions; such distribution is expected to
have two positions fully occupied and two with one-half occupation factor. However this is
not the case, the positions are overlapped twice so the maximum occupation factor is 0.82769
and the minimum factor is 0.67231. They were refined with restriction to give the proper
formula.
The most complicated disorder is found in 2a. Two symmetrically independent
molecules form two infinite chains. The first chain is ordered while the second one is totally
disordered. All attempts to resolve this disorder led to high R-factors and large maxima on
difference Fourier maps. Therefore the refinements were focused on the ordered part,
allowing the disordered molecules to acquire any geometry and displacement factors.
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Calculations. Prior to DFT optimizations, MM2-level systematic conformational
scans were performed by varying the torsional angles between the two carboxylic groups and
the central carbon atoms in increments of 5°, with 5 optimization steps performed in each
scan increment.
7
The minima obtained in the previous step were then optimized using the B3LYP
functional, which has been extensively used to produce good estimates of strain
energies.43,44,45,46 A 6-311+G(d,p) triple-split basis set was used, and diffuse functions were
included to describe both the effect of the chlorine atoms and the negatively charged
conjugate bases more accurately. Also, empirical corrections for long-range interactions
were done using Grimme´s dispersion with Becke-Johnson damping (B3BJ).47
To estimate pKa values, optimizations of 0, 1, 2a, 2x, 3z, 4x, 5, and 6 were repeated
using the B3LYP-D3BJ/6-311+G(d,p) method in conjunction with Truhlar´s SMD implicit
solvent model,48 followed by frequency calculations. In order to improve the description of
solvation, two explicit water molecules were added to all structures.49,50 These water
molecules were always placed the same manner, each forming a single hydrogen bond with a
different carboxylic group. The number of analyzed conformers grew substantially: starting
from each gas-phase geometry of a neutral compound, up to four different conformers for
monoanions and another four for dianions were constructed. However, the resulting relative
energies of different conformers were generally very similar (within 0.4 kcal/mol). The same
method was used for the radical involving paths with the appropriate solvents (CCl4 and
benzene).
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For all above mentioned calculations, only the lowest energy structure of each
compound was used. These calculations were done using Gaussian 09.51
NMR chemical shifts and coupling constants were calculated using B3LYP
functional, 6-31G(d,p) basis set and polarizable continuum model used for implicit acetone
solvation.52,53 The Gaussian 16 program package was used for the NMR calculations.54
Measurements of pKa. Capillary electrophoresis (CE) experiments were performed
on a CE 7100 analyzer (Agilent, Waldbronn, Germany) equipped with UV-vis
spectrophotometric diode array detector set at 200 nm and bare fused silica capillary with
outer polyimide coating: id/od 50/375 μm, total/effective (to the detector) length 480/395
mm, Polymicro Technologies, Phoenix, AZ, USA.
Synthesis. Hydrolysis of Methyl Esters (GP1). Dimethyl esters 8, 9a, 9x, 10z, and
11x (1 equiv.) were dissolved in wet THF (6 mL) and LiOH.H2O (10 equiv.) followed by
water (4 mL) was added to the reaction mixture. The slightly yellowish solution was stirred
for 60 min at room temperature. Subsequently, THF was removed under reduced pressure
and the aqueous phase was acidified with concentrated aqueous HCl to pH ~1. White dense
solid precipitated in most cases. The aqueous phase was extracted with ether (3 × 25 mL)
and the colorless organic phase was dried over MgSO4. The solvent was removed under
reduced pressure and the slightly yellowish solid residue was triturated with CH2Cl2 (3 ×
2 mL), hexane (3 × 2 mL), and finally thoroughly dried under reduced pressure (60 min, 600
mTorr). Diacids 1, 2a, 2x, 3z, and 4x were obtained as white or slightly grayish crystalline
solids.
2-Chlorobicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (1) was prepared from 8 (90
mg, 0.412 mmol) and LiOH.H2O (173 mg, 4.120 mmol) in a mixture of THF (6 mL) and
water (4 mL) according to GP1. Compound 1 was obtained as a grayish crystalline solid (68
mg, 0.357 mmol, 87%).
1
Mp > 243 °C (dec.). H NMR (400 MHz, acetone-d6): δ 2.23 (dd, J1 = 2.7 Hz, J2 =
9.9 Hz, 1H), 2.37 (dd, J1 = 2.9 Hz, J2 = 7.0 Hz, 1H), 2.64 (d, J = 2.7 Hz, 1H), 3.00 (dd, J1 =
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2.9 Hz, J2 = 9.9 Hz, 1H), 4.66 (d, J = 7.0 Hz, 1H), 9.89 (br s, 2H). 13C {1H} NMR
(100 MHz, acetone-d6): δ 44.6, 47.9, 48.9, 71.4, 167.7. IR (KBr): 3029, 2987, 2919, 2612,
1706, 1502, 1428, 1339, 1300, 1221, 1089, 1059, 1014, 927, 811, 748, 599, 529, 472 cm-1.
MS, m/z (%): 189.0 (100, center of isotope cluster, M - H). HRMS (ESI-) m/z: [M - H]-
Calcd for C7H6ClO4 188.9960; Found 188.9961. Anal. Calcd. for C7H7ClO4: C, 44.12; H,
3.70. Found: C, 44.26; H, 3.75.
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(1RS, 2rs, 3SR, 4sr)-2,4-Dichlorobicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (2a)
was prepared from 9a (120 mg, 0.474 mmol) and LiOH.H2O (199 mg, 4.740 mmol) in a
mixture of THF (6 mL) and water (4 mL) according to GP1. Compound 2a was obtained as
a grayish crystalline solid (97 mg, 0.431 mmol, 91%).
1
Mp > 263 °C (dec.). H NMR (400 MHz, acetone-d6): δ 2.33 (dd, J1 = 4.0 Hz, J2 =
7.5 Hz, 1H), 3.32 (d, J = 4.0 Hz, 1H), 5.02 (s, 1H), 5.19 (d, J = 7.5 Hz, 1H), 9.84 (br s, 2H).
13C {1H} NMR (100 MHz, Acetone-d6): δ 44.2, 50.8, 66.8, 70.1, 165.3. IR (KBr): 3022,
2907, 2625, 2583, 1710, 1528, 1478, 1430, 1347, 1303, 1217, 1144, 1111, 1077, 1060, 1005,
944, 883, 774, 755, 734, 714, 692, 550, 492, 476 cm-1. MS, m/z (%): 223.0 (100, center of
-
isotope cluster, M - H). HRMS (ESI-) m/z: [M - H]- Calcd for C7H5Cl2O4 222.9570; Found
222.9572. Anal. Calcd. for C7H6Cl2O4: C, 37.36; H, 2.69. Found: C, 37.38; H, 2.67.
2,2-Dichlorobicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (2x) was prepared from
9x (200 mg, 0.790 mmol) and LiOH.H2O (331 mg, 7.900 mmol) in a mixture of THF (6 mL)
and water (4 mL) according to GP1. Compound 2x was obtained as a white crystalline solid
(172 mg, 0.764 mmol, 97%).
1
Mp > 255 °C (dec.). H NMR (400 MHz, acetone-d6): δ 2.58 (m, 2H), 2.94 (m, 2H),
9.65 (br s, 2H). 13C {1H} NMR (100 MHz, acetone-d6): δ 49.6, 53.6, 92.7, 165.7. IR (KBr):
3362, 3038, 2921, 2731, 2611, 2515, 1706, 1502, 1430, 1340, 1304, 1216, 1148, 1132, 1068,
1027, 1015, 942, 883, 862, 829, 789, 756, 724, 704, 648, 577, 524, 485, 433 cm-1. MS, m/z
(%): 223.0 (100, center of isotope cluster, M - H). HRMS (ESI-) m/z: [M - H]- Calcd for
-
C7H5Cl2O4 222.9570; Found 222.9571. Anal. Calcd. for C7H6Cl2O4: C, 37.36; H, 2.69.
Found: C, 37.23; H, 2.62.
(1RS, 3SR, 4sr)-2,2,4-Trichlorobicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (3z)
was prepared from 10z (400 mg, 1.391 mmol) and LiOH.H2O (584 mg, 13.910 mmol) in a
mixture of THF (6 mL) and water (4 mL) according to GP1. Compound 3z was obtained as
a white crystalline solid (332 mg, 1.280 mmol, 92%).
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Mp > 259 °C (dec.). H NMR (400 MHz, acetone-d6): δ 3.15 (dd, J1 = 4.6 Hz, J2 =
8.1 Hz, 1H), 3.40 (d, J = 4.6 Hz, 1H), 5.28 (d, J = 8.1 Hz, 1H). 13C {1H} NMR (100 MHz,
Acetone-d6): δ 45.6, 59.2, 68.7, 88.4, 163.3. IR (KBr): 3359, 3045, 2916, 2618, 2586, 2506,
1715, 1484, 1434, 1340, 1289, 1208, 1141, 1099, 1058, 1009, 922, 792, 748, 701, 602, 501,
442 cm-1. MS, m/z (%): 256.9 (100, center of isotope cluster, M - H). HRMS (ESI-) m/z: [M
-
- H]- Calcd for C7H4Cl3O4 256.9181; Found 256.9180. Anal. Calcd. for C7H5Cl3O4: C,
32.40; H, 1.94. Found: C, 32.38; H, 1.92.
2,2,4,4-Tetrachlorobicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (4x) was prepared
from 11x (200 mg, 0.621 mmol) and LiOH.H2O (261 mg, 6.210 mmol) in a mixture of THF
(6 mL) and water (4 mL) according to GP1. Compound 4x was obtained as a white
crystalline solid (160 mg, 0.544 mmol, 88%).
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Mp > 195 °C (dec.). H NMR (400 MHz, acetone-d6): δ 3.53 (s, 2H). 13C {1H} NMR
(100 MHz, acetone-d6): δ 49.7, 65.4, 87.5, 161.7. IR (KBr): 3373, 3030, 2867, 2601, 2510,
1718, 1432, 1296, 1230, 1182, 1093, 1020, 973, 933, 844, 794, 753, 713, 665, 541, 509, 489,
418 cm-1. MS, m/z (%): 292.9 (100, center of isotope cluster, M - H), 248.9 (52), 168.9 (63,
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centre of isotope cluster). HRMS (ESI-) m/z: [M - H]- Calcd for C7H3Cl4O4 290.8791;
Found 290.8789. Anal. Calcd. for C7H4Cl4O4: C, 28.61; H, 1.37. Found: C, 28.63; H, 1.38.
Bicyclo[1.1.1]pentane-1,3-dicarbonyl Dichloride (7).34 A suspension of 0 (2.000 g,
12.809 mmol) in SOCl2 (8.00 mL, 109.675 mmol) was refluxed 5 h at oil bath temperature of
100 °C. All solids slowly dissolved leaving a clear yellowish solution. Volatiles were
distilled off at atmospheric pressure and the same temperature. Kugelrohr distillation of the
yellow oily residue (130 °C, 600 mTorr) afforded 7 as colorless oil that immediately
crystallized (2.398 g, 12.424 mmol, 97%).
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Mp 58.3 - 60.0 °C (lit.34 55 - 57 °C). H NMR (400 MHz, CDCl3): δ 2.58 (s, 6H).
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13C {1H} NMR (100 MHz, CDCl3): δ 44.6, 54.8, 169.4.
Dimethyl 2-Chlorobicyclo[1.1.1]pentane-1,3-dicarboxylate (8). The published
procedure20 was adapted as follows. To a solution of 9x (115 mg, 0.454 mmol) in benzene-
d6 (10 mL) was added TMS3SiH (169 μL, 0.545 mmol, 1.2 equiv.) and AIBN (19 mg, 0.114
mmol, 25mol%) at room temperature. The clear colorless reaction mixture was stirred 6 h at
1
80 °C and 14 h at 60 °C. Reaction progress was monitored by H NMR (500 μL of the
reaction mixture was injected into an NMR tube and directly measured; the analyzed sample
was returned into the reaction mixture). Volatiles were removed under reduced pressure and
column chromatography on silica gel (hexane/ethyl acetate - 6:1) afforded 8 as a clear
colorless oil (93 mg, 0.425 mmol, 94%).
1H NMR (400 MHz, CDCl3): δ 2.17 (dd, J1 = 2.9 Hz, J2 = 9.9 Hz, 1H), 2.39 (dd, J1 =
3.1 Hz, J2 = 7.1 Hz, 1H), 2.58 (d, J = 2.9 Hz, 1H), 3.12 (dd, J1 = 3.1 Hz, J2 = 9.8 Hz, 1H),
3.73 (s, 6H), 4.52 (d, J = 7.1 Hz, 1H). 13C {1H} NMR (100 MHz, CDCl3): δ 43.9, 48.1, 48.7,
52.2, 70.4, 166.8. IR (KBr): 3009, 2956, 2916, 1738, 1649, 1500, 1438, 1373, 1304, 1214,
1163, 1142, 1058, 1021, 929, 919, 811, 789 cm-1. MS, m/z (%): 241.0 (100, M + Na).
HRMS (ESI+) m/z: [M + Na]+ Calcd for C9H11ClO4Na+ 241.0238; Found 241.0239. Anal.
Calcd. for C9H11ClO4: C, 49.44; H, 5.07. Found: C, 49.38; H, 5.00. (lit.27)
Dimethyl
(1RS,
2rs,
3SR,
4sr)-2,4-Dichlorobicyclo[1.1.1]pentane-1,3-
dicarboxylate (9a). To a solution of 10z (220 mg, 0.765 mmol) in benzene-d6 (15 mL) was
added TMS3SiH (283 μL, 0.918 mmol, 1.2 equiv.) and AIBN (31 mg, 0.191 mmol, 25mol%)
at room temperature. The clear colorless reaction mixture was stirred 12 h at 80 °C and 14 h
1
at 60 °C. Progress of the reaction was monitored by H NMR (500 μL of the reaction
mixture was injected into an NMR tube and directly measured; the analyzed sample was
returned into the reaction mixture). Volatiles were removed under reduced pressure and
column chromatography of the yellow residue on silica gel (hexane/ethyl acetate - 8:1) gave
9a as a clear colorless oil, which slowly crystallized (167 mg, 0.660 mmol, 86%).
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Mp 63.2 - 64.8 °C. H NMR (400 MHz, CDCl3): δ 2.20 (dd, J1 = 4.1 Hz, J2 = 7.5 Hz,
1H), 3.39 (d, J = 4.1 Hz, 1H), 3.78 (s, 6H), 4.67 (s, 1H), 5.22 (d, J = 7.5 Hz, 1H). 13C {1H}
NMR (100 MHz, CDCl3): δ 44.5, 50.0, 52.5, 65.9, 69.2, 164.4. IR (KBr): 3027, 3007, 2956,
2858, 1738, 1439, 1387, 1307, 1296, 1213, 1186, 1170, 1136, 1117, 1104, 1085, 1077, 1036,
1010, 959, 938, 922, 891, 876, 831, 804, 794, 767, 735, 723, 707, 566, 528 cm-1. MS, m/z
(%): 275.0 (100, M + Na). HRMS (ESI+) m/z: [M + Na]+ Calcd for C9H10Cl2O4Na+
274.9848; Found 274.9848. Anal. Calcd. for C9H10Cl2O4: C, 42.71; H, 3.98. Found: C,
42.74; H, 4.05.
Dimethyl 2,2-Dichlorobicyclo[1.1.1]pentane-1,3-dicarboxylate (9x).
The
published procedure27 was adapted as follows. A 500 mL three-necked round bottom flask
was charged with CCl4 (350 mL) that was then cooled to 0 °C and saturated for 1.5 h with
dry chlorine. Subsequently, a solution of 7 (2.202 g, 11.408 mmol) in CCl4 (20 mL) was
added and a clear yellow reaction mixture was irradiated with a 150 W incandescent bulb at 0
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- 5 °C for 22 h. Reaction progress was monitored by H NMR (400 μL of the reaction
mixture was injected into an NMR tube, 100 μL of CDCl3 was added and the sample was
immediately analyzed). Excess chlorine was purged by stream of argon (exhaust gas was
bubbled through 250 mL of saturated aqueous NaOH) until the yellow color of the reaction
mixture almost completely vanished (~20 min). Anhydrous methanol (5 mL) was added and
the reaction mixture was stirred at room temperature for 20 min. Solvents were removed
under reduced pressure. Column chromatography on silica gel (hexane/ethyl acetate - 3:1)
afforded the less polar trichloro derivative 10z (357 mg, 1.242 mmol, 11%), which was
eluted first, and then the expected dichloro derivative 9x (2.196 g, 8.677 mmol, 76%), both as
white crystalline solids.
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Mp 39.7 - 41.8 °C (lit. 42.0 - 42.5 °C27). H NMR (400 MHz, CDCl3): δ 2.48 (m,
2H), 3.01 (m, 2H), 3.80 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 49.6, 52.4, 52.7, 91.3,
164.9. IR (KBr): 3040, 3000, 2959, 2902, 2857, 1740, 1602, 1559, 1505, 1440, 1379, 1305,
1208, 1141, 1122, 1086, 1061, 1031, 1014, 960, 929, 859, 815, 801725, 620, 544, 504 cm-1.
MS, m/z (%): 253.0 (22, center of isotope cluster, M + H), 221.0 (34, center of isotope
cluster), 192.0 (17), 185.0 (100), 173.0 (14), 157.0 (13). HRMS (CI) m/z: [M + H]+ Calcd for
+
C9H11Cl2O4 253.0034; Found 253.0032. Anal. Calcd. for C9H10Cl2O4: C, 42.71; H, 3.98.
Found: C, 42.78; H, 4.02.
Dimethyl (1RS, 3SR, 4sr)-2,2,4-Trichlorobicyclo[1.1.1]pentane-1,3-dicarboxylate
(10z). A high-pressure 200 mL Schlenk flask was charged with dry CCl4 (150 mL) and the
solvent was cooled to 0 - 5 °C. Subsequently, chlorine was bubbled through for 20 min
followed by addition of 7 (2.398 g, 12.424 mmol) in CCl4 (10 mL). A clear brightly yellow
reaction mixture was irradiated for 16 h with a 500 W incandescent bulb from a distance of
1
10 - 15 cm at 60 - 65 °C. Reaction progress was monitored by H NMR (400 μL of the
reaction mixture was mixed with 100 μL of CDCl3 directly in the NMR tube and immediately
analyzed). Volume of the reaction mixture was reduced to ~30 mL by distillation at
atmospheric pressure and oil bath temperature of 90 °C. Methanol (10 mL) was then added
into the reaction mixture and the solution was refluxed for 30 min. Volatiles were removed
under reduced pressure and column chromatography on silica gel (hexane/CH2Cl2 - 1:3)
afforded 10z (2.250 g, 7.826 mmol, 63%), and 9x as a more polar side product (209 mg,
0.826 mmol, 7%), both as a white crystalline solids.
1
Mp 68.3 - 69.1 °C. H NMR (400 MHz, CDCl3): δ 3.17 (dd, J1 = 4.5 Hz, J2 = 8.0 Hz,
1H), 3.41 (d, J = 4.5 Hz, 1H), 3.83 (s, 6H), 5.21 (d, J = 8.0 Hz, 1H). 13C {1H} NMR
(100 MHz, CDCl3): δ 45.3, 52.8, 58.2, 67.9, 87.5, 162.5. IR (KBr): 3044, 3013, 2960, 2859,
1739, 1480, 1443, 1301, 1206, 1187, 1137, 1099, 1077, 1059, 1010, 977, 952, 929, 918, 889,
815, 790, 751, 718, 597 cm-1. MS, m/z (%): 308.9 (100, M + Na). HRMS (ESI+) m/z: [M +
Na]+ Calcd for C9H9Cl3O4Na+ 308.9459; Found 308.9457. Anal. Calcd. for C9H9Cl3O4: C,
37.60; H, 3.16. Found: C, 37.50; H, 3.15.
Dimethyl
2,2,4,4-Tetrachlorobicyclo[1.1.1]pentane-1,3-dicarboxylate
(11x).
CAUTION: Reaction involves manipulation with a highly toxic and corrosive gas under high
pressure and should be performed only by trained personnel! A high-pressure Schlenk flask
was charged with a solution of 7 (480 mg, 2.487 mmol) in CCl4 (4 mL). Subsequently,
chlorine (~10 mL) was condensed into the reaction mixture at -78 °C. Cooling was stopped
and the clear yellow solution was irradiated with a 500 W incandescent bulb from the
distance of 6 - 10 cm for 16 h at 50 °C. Progress of the reaction was monitored by 1H NMR
(100 - 200 μL of the reaction mixture was cannulated/sucked into NMR tube immersed in
liquid nitrogen. Excess of chlorine was allowed to evaporate and the volume of the solution
was adjusted with CDCl3 to ca 500 μL.). Irradiation was stopped and the reaction mixture
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was cooled to -50 °C. Cooling was then interrupted, chlorine was allowed to slowly
evaporate, and releasing gas was trapped in saturated aqueous NaOH (400 mL). Remaining
chlorine was purged by stream of argon at room temperature for 5 min. Methanol (8 mL)
was then added and the reaction mixture was stirred at the same temperature for additional 15
min. Solvents were removed under reduced pressure and column chromatography on silica
gel (hexane/ethyl acetate - 3:1) yielded 11x as a clear colorless oil that slowly solidified (595
mg, 1.848 mmol, 74%).
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Mp 55.1 - 56.4 °C. H NMR (400 MHz, CDCl3): δ 3.47 (s, 2H), 3.91 (s, 6H). 13C
{1H} NMR (100 MHz, CDCl3): δ 49.0, 53.1, 64.4, 86.8, 160.9. IR (KBr): 3023, 2961, 2903,
2857, 1744, 1700, 1476, 1439, 1385, 1307, 1199, 1170, 1099, 1083, 1036, 1014, 981, 935,
926, 837, 823, 808, 800, 746, 663, 613, 511, 490 cm-1. MS, m/z (%): 344.9 (100, centre of
+
isotope cluster, M + Na). HRMS (EI) m/z: [M+] Calcd for C9H8Cl4O4 319.9177; Found
319.9182. Anal. Calcd. for C9H8Cl4O4: C, 33.57; H, 2.50. Found: C, 33.49; H, 2.38.
Hydrolysis of 9 with NaOH in Water. Diester 9x (2.196 g, 8.677 mmol) was
suspended in aqueous NaOH (2.000 g, 50.000 mmol in 50 mL). The white suspension was
intensely stirred 5 h at 50 °C. The solid slowly dissolved leaving a brownish solution. The
reaction mixture was cooled to room temperature and washed with CHCl3 (3 × 30 mL). The
brownish aqueous phase was acidified using concentrated aqueous HCl to pH ~1, and
extracted with ether (5 × 25 mL). The clear yellowish organic phase was dried over Na2SO4
and solvent was removed under reduced pressure. The yellowish solid residue was dissolved
in a minimal amount of ether and 2x was precipitated with pentane in form of a white
crystalline solid (1.080 g, 4.799 mmol, 55%). Analytical sample was obtained by
recrystallization from CHCl3.
The yellowish organic phase obtained after precipitation of 2x was treated at room
temperature with ethereal CH2N2 until evolution of gas stopped and the organic phase
remained permanently yellow. Solvents were removed under reduced pressure and column
chromatography on silica gel (hexane/ethyl acetate - 5:2) afforded 13 as a clear slightly
yellowish oil (365 mg, 1.556 mmol, 18% based on 9x).
1
Dimethyl 2-Chloro-3-(hydroxymethyl)cyclobut-1-ene-1,3-dicarboxylate (13). H
NMR (500 MHz, CDCl3): δ 2.90 (ddd, J1 = 18.3 Hz, J2 = 2.1 Hz, J3 = 1.0 Hz, 1H), 2.91 (ddd,
J1 = 17.0 Hz, J2 = 2.0 Hz, J3 = 1.0 Hz, 1H), 3.25 (ddd, J1 = 17.0 Hz, J2 = 2.1 Hz, J3 = 1.6 Hz,
1H), 3.35 (ddd, J1 = 18.3 Hz, J2 = 2.1 Hz, J3 = 1.5 Hz, 1H), 3.78 (s, 3H), 3.84 (s, 3H). 13C
{1H} NMR (125 MHz, CDCl3): δ 46.2, 51.4, 52.6, 53.0, 76.3, 124.9, 138.9, 163.0, 174.9. IR
(KBr): 3477, 3002, 2956, 2848, 1730, 1631, 1439, 1344, 1284, 1246, 1217, 1072, 1053,
1003, 955, 901, 816, 764 cm-1. GC-MS, m/z (%): 235 (2, M + H), 216 (41, M - H2O), 203 (6,
M - OCH3), 185 (16), 175 (18), 157 (12), 146 (13), 139 (53), 127 (22), 115 (73), 111 (55), 87
(44), 77 (33), 59 (100, COOCH3), 53 (24). HRMS (ESI+) m/z: [M + Na]+ Calcd for
C9H11ClO5Na+ 257.0187; Found 257.0187.
ASSOCIATED CONTENT
Supporting Information
1
13
Copies of H and C NMR spectra of all new compounds, CIFs and ORTEP views of a
single molecule and packing in 1, 2x, 3z, 4x, 9a, 9x, and 10z, optimized geometries of all
chlorinated bicyclo[1.1.1]pentanes and parent 0 that were used for computation of the strain
energies and pKa values, and geometries and energies of all structures used in Schemes 6, 7
and 8.
AUTHOR INFORMATION
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Corresponding Author
* kaleta@uochb.cas.cz
ORCID
J. Kaleta: 0000-0002-5561-7580
7
I. Císařová: 0000-0002-9612-9831
M. Dračínský: 0000-0002-4495-0070
J. Michl: 0000-0002-4707-8230
V. Kašička: 0000-0003-1719-1432
V. Šolínová: 0000-0003-0379-8428
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
Acknowledgment is made to the Donors of the American Chemical Society Petroleum
Research Fund for partial support of this research under award PRF 56668-ND4. This work
was also supported by the Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic (RVO: 61388963), Czech Science Foundation (grant no. 17-
10832S), and the grant MOBILITY 7AMB (7AMB16FR038). Access to computing and
storage facilities owned by parties and projects contributing to the National Grid
Infrastructure MetaCentrum provided under the programme „Projects of Large Research,
Development, and Innovations Infrastructures“ (CESNET LM2015042), is greatly
appreciated. We are grateful to Dr. Lucie Bednárová for help with IR spectra, Prof. Lubomír
Pospíšil for preliminary pKa measurements, and Dr. Jacek Pecyna for performing preliminary
experiments.
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