Studies of Metaphosphate Acids and Metaphosphate
Anhydrides in Aprotic Media
MASSACHUSETTE9
INSTITUTE
OF TECHNOLOLGY
by
JUN 24 2015
Khetpakorn Chakarawet
Submitted to the Department of Chemistry
in partial fulfillment of the requirements for the degree of
LIBRARIES
Bachelor of Science in Chemistry
at the
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
June 2015
@ Massachusetts Institute of Technology 2015. All rights reserved.
Signature redacted
. . .......
.. .. ....
.
Author ..................
Department of Chemistry
May 8, 2015
Signature. .redacted
, .................
C ertified by ................................
Christopher C. Cummins
Professor of Chemistry
Thesis Supervisor
Accepted by ............
Signature redacted
Rick L. Danheiser
A. C. Cope Professor of Chemistry
Undergraduate Officer, Department of Chemistry
2
Studies of Metaphosphate Acids and Metaphosphate
Anhydrides in Aprotic Media
by
Khetpakorn Chakarawet
Submitted to the Department of Chemistry
on May 8, 2015, in partial fulfillment of the
requirements for the degree of
Bachelor of Science in Chemistry
Abstract
The chemistry of metaphosphate acids has historically been studied in aqueous media, where acid-catalyzed hydrolysis and solvent leveling effects of these strong acids
have prevented their observations and rigorous characterization. Solubilization of tri-,
tetra-, and hexametaphosphates in aprotic media using the IPPN + cation ([PPNI+
bis(triphenylphosphine)imninium) has revealed the rich acid chemistry of metaphosphates that has previously been elusive in aqueous media. Protonation of imetaphosphates in organic media has resulted in six metaphosphate acids. X-ray diffraction
studies display that the structural configurations of metaphosphate acids are dictated
by strong hydrogen bonding interactions. As a consequence of anti-cooperative effect, intramolecular hydrogen bonds are preferred at low degrees of protonation, and
intermolecular hydrogen bonds are preferred at high degrees of protonation, resulting
in oligomeric and polymeric structures. Because of the symmetry of the hydrogen
bonds in metaphosphate acids, Low-Barrier Hydrogen Bonds (LBHB) are formed if
the conformation of the metaphosphate ring allows.
Metaphosphate anhydrides result fron the dehydration of metaphosphate acids.
They can undergo hydrolysis to regenerate metaphosphate acids, or alternatively
alcoholysis to generate metaphosphate esters. Alcoholysis of metaphosphiate anhydrides presents a novel method to quantitatively phosphorylate organic substrates, of
particular interest are substrates of biological significance such as nucleosides. The
phosphorylating ability of metaphosphate anhydrides makes them promising candidates for biological phosphorylation.
Thesis Supervisor: Christopher C. Cummins
Title: Professor of Chemistry
3
4
Acknowledgments
I would like to express my gratitude to my thesis superadvisor Professor Kit Cummins.
I have learned tremendously from his guidance throughout my undergraduate career.
Starting from knowing nothing about chemical research, I am grateful that he took
me into the lab, and has taught mue quality research ever since. The challenges he put
up for me, from giving a group meeting to presenting at a Symposium, have greatly
helped ime develop as a better scientist. I also appreciate his kindness in taking me
to explore the beaches, dinings, and bowling places around Boston area in group
outings. Most importantly, I am thankful for the freedom he has given me to pursue
my research for the past years, which has cuinminated in this thesis.
My appreciation extends to the imembers of the Cummins group: Cesar Manna,
my first postdoc supervisor, who has taught me chemistry and introduced me to
the real world of research and life; Nazario Lopez, for advising me with various lab
techniques and simply being such a great friend; Yanfeng Jiang, my second postdoc
supervisor, who shared his wisdom, experience, and good tine, and who started this
project; A. Laura Kohout for laying down solid fundamentals for the work in Chapter
2; Alexandra Velian for her part-time mentorship about chemistry and life in general;
Julia Stauber, Matthew Nava, loana Knopf, Wesley Transue for helpful discussions
whenever I needed; and Eric Bloch for my graduate school decision.
I would like to thank all of miy friends who share a part of their lives, going through
roughness and joyfulness with me at MIT. Special thanks to Supanat Kamtue and
Pasin Manurangsi for the adventure throughout our four years, and Thipok Rakammouykit who has been a reliable partner working together.
Lastly and importantly, I aim grateful to my family for their supports to come to
the United States and MIT, for their understandings and freedoi for me to pursue
my own interests, and for the cares they have given to me. Without their supports,
I would not be where I am today.
5
6
Contents
1
2
Synthesis and Characterizations of Metaphosphate Acids
17
1.1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
1.2
General Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
1.3
Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . .
20
1.3.1
Synthesis of IPPNI 2VP 3O 9 Hi (1) . . . . . . . . . . . . . . . . .
20
1.3.2
Synthesis of [PPN12[P 4 0 12 H 2 ] (2) . . . . . . . . . . . . . . . .
20
1.3.3
Synthesis of [PPN]4[(P 4 0 12 ) 3Hs] (3) . . . . . . . . . . . . . . .
20
1.3.4
Synthesis of [PPN]4[P 6 0 1 8 H 2 J.2H 2 0 (4) . . . . . . . . . . . . .
22
1.3.5
Synthesis of IPPN 3 [P6 OsH 3] (5) . . . . . . . . . . . . . . . .
23
1.3.6
Synthesis of [PPNJ 2 [P 6 0 1 8H 2 (H 30) 2j (6)
. . . . . . . . . . . .
23
1.3.7
Structures of Metaphosphate Acids and Hydrogen Bonding . .
24
1.4
Conclusions
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
1.5
Experimental Details and Procedures . . . . . . . . . . . . . . . . . .
30
Synthesis of Metaphosphate Anhydrides and Alcoholysis Reactions 41
2.1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
2.2
Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . .
43
2.2.1
Synthesis of IPPN12IP4011 (7) . . . . . . . . . . . . . . . . . .
43
2.2.2
Alcohiolysis of [PPN] 2 [P 4 01 11 . . . . . . . . . . . . . . . . . . .
44
2.2.3
Synthesis of IPPN] 3 [P6 0
(8) . . . . . . . . . . . . . . . . .
46
17 H]
2.3
Conclusions
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
2.4
Experimental Details and Procedures . . . . . . . . . . . . . . . . . .
48
7
A Determination of Acid Dissociation Constant of [PPN] 2 [P 4 0 1 2 H 2 ] in
Acetonitrile Solution
53
B Optimized Geometry of [P 6 01 SH 2 (H3 0) 2
References
2
~
57
59
8
List of Figures
. . . . . . . . . . . . . . . . . . . . .
18
. . . . . . . . . . . . . . .
25
H2 ] . . . . . . . . . . . . . .
25
Examples of metaphospliate
1-2
Solid-state structure of IPPNI 2 tP3 0 9 HI
1-3
Solid-state structure of [PPN]2[P 4 0
1-4
Solid-state structure of VPPN]4[(P4012) 3H8 ] .
1-5
Solid-state structure of [PPN 4 [P 6 0isH2J+2H 2 0 . . . . . . . . . . .
1-6
Solid-state structure of {PPN]31P 6 0 18 H 3]
1-7
Solid-state structure of [PPN] 2 [P6 0 18 H 2 (H 3 0) 21
2-1
Solid-state structure of fPPN] 2 [P 4 0u.
.
26
.
28
.
...............
28
.
. . . . . . . . . . . . . .
29
.
12
.
.
1-1
. . . . . . . . . . . . . . . .
44
A-1 UV-vis spectra of spectrophotometric titration of [PPN]2[P 4 0 1 2 H 2 ]
54
Calculated structure of [P 6 0 1 8 H 2 (H 30) 212 . . . . . . . . . . . . .
9
.
B-i
. . . . . . . . . .
58
10
List of Tables
H2I . . . .
1.1
Crystallographic data for IPPN]2[P 3 0 9 H] and [PPN12[P 4 0
1.2
Crystallographic data for [PPN] 4 [(P 4 01 2 ) 3 Hs] and [PPN]4[P6 0 18 H 2]-
12
.2H 20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
39
1.3
Crystallographic data for [PPN]3[P 6 OlsH 3 ] and [PPN]2[P 6 OisH 2 (H 3 0) 21 40
2.1
Crystallographic data for [PPN]2[P 4 OuI
11
. . . . . . . . . . . . . . . .
51
12
List of Schemes
1.1
Synthesis of [PPN1 2 P 3 09 H]
1.2
Synthesis of [PPN]2{P 4 0
. . . . . . . . . . . . . . . . . . . . . . .
20
. . . . . . . . . . . . . . . . . . . . . .
21
1.3
Synthesis of [PPN4[(P 4 0 12 ) 3 H8 ] . . . . . . . . . . . . . . . . . . . . .
21
1.4
Synthesis of [PPN]4[P 6O 18H 2 ]-2H 2 0
. . . . . . . . . . . . . . . . . . .
22
1.5
Synthesis of [PPN]3tP6 O 1sH 3 ] . . . . . . . . . . . . . . . . . . . . . .
23
1.6
Synthesis of [PPN] 2 [P6 01 SH 2 (H 3 0) 21
24
2.1
Hydrolysis of 1,5-p-oxo-tetraretaphosphate
2.2
Synthesis of [PPN] 2 [P 4 0uI and hydrolysis reaction
2.3
Synthesis of [PPNI 2 [P 4 01o(OH)(OMe)]
2.4
Synthesis of cholesteryl hydrogentetramnetaphosphate
2.5
Synthesis of [PPN] 3 [P6 0
12
H2]
17H]
. . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . .
42
. . . . . . . . . .
43
. . . . . . . . . . . . . . . . .
44
. . . . . . . . .
45
. . . . . . . . . . . . . . . . . . . . . . .
47
13
14
List of Abbreviations
2,4-DNP
2,4-dinitrophenol
A
angstrom
Ar
aromatic
ATR
Attenuated Total Reflection
br
broad
c111-
wavenumber
DCC
N,N'-dicyclohexylcarbodiimnide
DCM
dichloromethane
DCU
N,N'-dicyclohexylurea
dd
doublet of doublets
6
chemical shift
DME
1,2-dimethoxyethane
equiv
equivalent
ESI-MS
Electrospray Ionization Mass Spectrometry
Et
ethyl
g
gram
Ih
hour
IR
Infrared Spectroscopy
J
NMR. coupling constant
K
Kelvin
Ka
acid dissociation constant
A
wavelength
LBHB
Low-Barrier Hydrogen Bond
15
M
molar
m
multiplet (NMR), inedium (IR)
MeCN
acetonitrile
imnol
imillimole
/,L
microliter
11111
nanometer
NMR
Nuclear Magnetic Resonance
V
vibrational frequency
OTf
trifluoromethane sulfonate
ppm1
parts per million
PPN
bis(triphienylphosphine)iiiinium
s
singlet (NMR), strong (IR)
t
triplet
td
triplet of doublets
TFA
trifluoroacetic acid
TFAA
trifluoroacetic anhydride
TfOH
trifluoromethane sulfonic acid
THF
tetrahydrofuran
UV-vis
Ultraviolet-visible
16
Chapter 1
Synthesis and Characterizations of
Metaphosphate Acids
1.1
Introduction
Phosphates are aii ubiquitous class of compounds found in various sources from rocks
to living beings.
The chemical properties of phosphates play an essential role in
encoding the information of life through formation of nucleotides and nucleic acids.
1
Additionally, phosphates are well-known for their ability to engage in hydrogen bonding, giving rise to their rich chemistry involving non-covalent interactions.
2
The abil-
ity of orthophosphate to be protonated at ambient pH and biological pH leads to the
well-studied chermistry associated with orthophosphate and its conjugate acids.
Metaphosphate is a cyclic oligomer of phosphates with an erpirical formula
(P03 )- and is formed from the condensation of orthophosphate.
Fig.
1-1 shows
examples of metaphosphate with three, four, and six monomeric units. Despite being
known for two centuries, metaphosphate chemistry has been predominantly limited
at their fully deprotonated anions.3
As opposed to orthophosphate, little is known about the acid chemistry of metaphosphates. Determination of pKa of trimetaphosphate and tetrametaphosphate in aqueous solution indicated the strong acidity of the last proton of trimetaphosphate
(pKa3 = 0.65
0.10) and of tetrametaphosphate (pKa4 = 1.53
17
0.08).4 How-
0
0
\~ /_
O=P
P-6
I
1
0-
0
/P
0
0
| O--P-O/0
-
d
O---
0
P
0 0
K.
//
0
0/
0 \
/
/
0
\
Po
-o
00
0
0-
a
b
c
1P 3 0 913 -, (b) tetra-
-
Figure 1-1: Examples of metaphosphate: (a) trimetaphosphate
metaphosphate fP 40 1 2 14-, (c) hexametaphosphate IP6 OsI 6
ever, mnetaphosphates are known to undergo hydrolysis reaction in acidic solution to
give linear polyphosphates and phosphoric acid.' The strong acidity of protonated
imetaphosphates and the hydrolytic instability of metaphosphates have so far prevented rigorous isolation or characterization of protonated metaphosphates in aqueous
media.
Preparation of protonated inetaphosphate, herein will be referred to as metaphosphate acid, in aqueous solution has not been successful. Nonetheless, the first synthesis of rnetaphosphate acids was made possible through solid-state furnace reaction. 6
The first structure of metaphosphate acid, Na 2 [P 309 H], was reported in 1983,
and
until the time of this study only two structures of metaphosphate acids are known. 8
The elusiveness of metaphosphate acids is attributed to their strong acidity and leveling effect of strong acids in water, thus rendering the conventional study in aqueous
solution fruitless.
1.2
General Methodology
Bis(triphenylphosphine)iminiumn ([PPN] +) cation was employed to solubilize metaphosphate anions in organic solvents such as acetonitrile (MeCN) and acetone.
Non-
aqueous solvents are important for the study of retaphosphate acids because of the
instability of metaphosphate in acidic aqueous solution. Herein, netaphosphate acid
can be facilely synthesized from protonation of the corresponding metaphosphate
18
anion with strong organic acid in aprotic solvent. Trifluoroacetic acid (TFA) and trifluoromethane sulfonic acid (TfOH) are potent reagents to synthesize inetaphosphate
acids because of their strong acidity and availability in anhydrous forms.
More-
over, they were purposefully chosen based on the different solubility of the byproduct
IPPN{CF 3 COO] or [PPNI[OTf] from the resulting mnetaphosphate acids, which
enables purification of inetaphosphate acids from the byproducts by simple solvent
washing.
The use of [PPNI+ as countercation provides three advantages.
First, [PPN+
cation generally helps improve the crystallinity of the product. Single crystals suitable
for X-ray diffraction of several compounds have been obtained with this countercation.
Second, [PPNI+ cation cannot participate in classical hydrogen bonding,
9 thus en-
abling the observations of hydrogen bonds in the metaphosphate acids uninterrupted
by their countercations. Third, IPPNI+ salt of metaphosphates and metaphosphate
acids are insoluble in ethereal solvents, while [PPN][CF 3 COO] and [PPNI[OTf] are
soluble in solvents such as tetrahydrofuran (THF) and 1,2-dimethoxyethane (DME),
resulting in the convenient purification of the product.
In conclusion, the advantages of the methodology described herein allow us to:
1. Avoid the use of aqueous solvent and prevent hydrolysis of metaphosphates
2. Synthesize metaphosphate acids in solution and gain more control over the
product distribution compared to solid-state reaction
3. Facilely separate byproduct of the reaction by simple solvent washing
4. Improve crystallinity of the products
5. Observe hydrogen bonding iii metaphosphate acids with minimal interactions
to the countercation
6. Study the reactivities of metaphosphate acids in solution
19
1.3
1.3.1
Results and Discussion
Synthesis of [PPN]2[P30 9H] (1)
Monohydrogen trimetaphosphate was synthesized from the addition of TFA to a solution of [PPN1 3 1P 3 O9].H 2 0 in MeCN (Scheme 1.1). Addition of THF to the reaction
mixture resulted in 1 crystallizing out as block-shaped crystals in 80% yield.
3
The
1p{ 1 H} NMR spectrum of 1 features a broad signal at 6 -20.43 ppm, indicative of
fast proton exchange among the phosphate units.
10
The 1 H NMR (CD 3CN) spectrum
features the signal of the acidic proton at 6 12.55 ppm.
7 (PPN+) 3
-
o'
O
H2 0
-
MeCN- [PPN][CF 3COO]
K7OO
0
CF 3COOH
O
p
7
0
011111H
(PPN+) 2
-
0
0
o
oI
\
- H 20
0
o
.-- P
0
0
Scheme 1.1: Synthesis of [PPN1 2 1P 309H] from [PPNI 3 [P 3O9].H 2 0 and TFA. Hydrogen
bond is shown in dashed line.
1.3.2
Synthesis of [PPN] 2 [P 4 0 12 H 2 ] (2)
Dihydrogen tetrametaphosphate was synthesized from the addition of trifluoroacetic
anhydride (TFAA) to a suspension of [PPNI 4 [P 4 012I-5H 2 0 in acetone (Scheme 1.2).
Due to the limited solubility of 2 in acetone, the product precipitated out of the
reaction mixture as a white solid in 94% yield. The
31
P{1 H} NMR spectrum features a
broad signal at 6 -25.14 ppm indicative of fast proton exchange among the phosphate
units. The 1H NMR (CD 3CN) spectrum features the signal of the acidic proton at 6
14.01 ppm. The pKa of 2 in MeCN was determined to be 15.83
1.3.3
0.11 (Appendix A).
Synthesis of [PPN]4[(P 4 01 2 ) 3H] (3)
Treatment of IPPN1
2 IP 4 0 12 H 2 ]
with TFA did not result in further protonation of 2
because the pKa of the conjugate acid of 2 is significantly lower than that of TFA
20
7 (PPN*) 4
~7I (PPN)
O
5H20
0
eH
(CF 3CO) 2 0
acetone
o
o
06
0
0
O'-O-P-==O
- 2 (PPN][CF3COO]
-5 H20
1=::
----
Scheme 1.2: Synthesis of [PPN121P 4 01 2 H 2 ] from
-
(J-IH\\",\\o
/
o
2
-
0
5H,,O
[PPN]4[P 4 O12].5H 20 and TFAA in
acetone. Hydrogen bonds are shown in dashed lines.
(pKa = 12.65 in MeCN"). Alternatively, addition of TfOH to an MeCN solution
of 2 resulted in a new product octahydrogen tris(tetrametaphosphate) (Scheme 1.3).
Addition of DME to the reaction mixture resulted in the product crystallizing out as
1
3
blade-shaped colorless crystals in 71% yield. The
p{1 H} NMR spectrum features
a very broad signal at 5 -30.06 ppm, indicating fast proton exchange of the cluster.
The 'H NMR (CD 3CN) spectrum contains a very broad signal attributed to the acidic
protons at 6 13.73 pprm.
(PPN')4
0
0
0
H
O\
7 (PPN+) 2
H
SH
0
H
H
0
0
0O
|
O...-P"=O
O I_H NN O
+ 2/3 TfOH
MeCN
0-0
0
/'0
0
H
0
O--P
,[1/3
- 2/3 [PPN][OTf]
-
0
-H
HE
O0
0
/
\
1
P.---O-Qp
0 //\
0
0
Synthesis of IPPN]4[(P 4 0 12 ) 3 Hs] from the protonation of [PPN] 2
-
Scheme 1.3:
H
[P 4 0 12 H 2 1 with TfOH. Strong hydrogen bonds are shown in dashed lines.
21
3 is kinetically stable in solid state. However, in MeCN solution, it decomposes
within 4 h, thus preventing accurate molecular weight determination in the solution
phase. The decomposition is accompanied by new signals in
at 6 -27.15
1.3.4
(s) and -28.17
31
P{ 1 H} NMR. spectrum
(m) ppm.
Synthesis of [PPN] 4 [P 6 01H2]-2H 2 0 (4)
[PPN]4[P 6 O 1 sH2]-2H20 was prepared from cation exchange of Li[P6 OisJ with {PPNCL
in water (Scheme 1.4). The product precipitated out of the reaction mixture as a
white solid. The crude material after cation exchange is a [PPN + salt of a partially
protonated hexametaphosphate.
It can be fully converted to 4 by crystallization
from MeCN/THF cosolvents. 4 can be isolated as block-shaped crystals in 66% overall yield.
The
31
p{1 H} NMR spectrum features a broad signal at 6 -24.95
ppm
corresponding to the protonated hexametaphosphate ring undergoing fast proton exchange. The
1
H NMR (CD 3 CN) spectrumn features the signal of acidic protons at 6
12.53 ppm.
0
/.
H
Li 6[P 6 0 18] + 4 [PPN]CI
H 20
(PPN') 4
H---O
IN
1 0
p
H
-4 LiCI
-2 Li-, - 2
OH-
C 00
0
O
P
/ X,
0
0
0 .... H-O
Schemie 1.4: Synthesis of [PPN] 4 [P6 0 1 8 H 2]-2H 2 0 fron Li 6 [P6 0 1 8 1 and tPPNICl. Hydrogen bonds are shown in dashed, and strong hydrogen bonds in thick dashed lines.
The fact that [P 6 0 18 ]6- can be protonated by water is consistent with the increasing basicity of cyclic phosphates of increasing ring sizes 4 In fact, dilydrogeni
hexametaphosphate has been reported crystallographically with 3,5-xylidiiiun and
2-amino-5-chloropyridiiiui cations prepared from aqueous solution.
22
8,12
Synthesis of [PPN]3dP6 Oi8 H3 (5)
1.3.5
Protonation of [PPN]4[P 6 O 1 8 H 2 J.2H2 0 with TFA in MeCN solution produced 5 in
87.6% yield (Scheme 1.5). The
at 6 -28.09
3
1
p{ 1 H} NMR spectrum of 5 features a broad signal
ppm, and the 1H NMR (CD 3CN) spectrum features a broad signal of
acidic protons at 6 15.20 ppm. The up-field shifted
31
P NMR chemical shift and
down-field shifted 1H NMR chemical shift indicate further protonation of 4.
O-H-..
(PPN') 4
(PPN*) 3
HII0
-'P
&
\
H
H
/
p.P..
MeCN
p
'
0-,_
d'-
RN
3 COOH
/\CF
V
P-.O
\
0\
-
[PPN][CF 3 COO]
H-
O=P-- O
=
'
o
Scheme 1.5: Synthesis of [PPN]3[P 6 OisH 3] fron [PPN]4[P6 OisH 2 ].2H 2 0 and TFA.
Strong hydrogen bonds are shown in thick dashed lines.
1.3.6
Synthesis of [PPN] 2[P6 0 18 H2 (H3 0) 21 (6)
In MeCN solution, treatment of 4 with excess TFA resulted in the quantitative formation of 5 with no other phosphate-containing products. The observation indicated
that the pKa of the conjugate acid of 5 must be significantly lower than that of
TFA, which is also the case observed in tetrametaphosphiate system of 2. However, in
-
acetone solution, protonation of [PPN] 4 [P6 OisH 2 ] 2H 20 with TFA resulted in [PPN] 2
[P 6 0 1 8 H 2 (H 3 0) 2 precipitating out as a solid in 75.7% yield (Scheme 1.6). TFA does
not protonate the hexametaphosphate ring, but rather water molecules in the solution. Precipitation of the product is the driving force that enables the synthesis of
6, as opposed to the similar reaction done in MeCN which instead produces 5. The
3 1 p{'H}
NMR spectrum of 6 features a broad signal at 6 -27.34 ppm, and the 1H
NMR (CD 3 CN) spectrum features a very broad signal of acidic protons at 6 13.48
ppm.
23
O
H0
(PPN+)2
-
(PPN') 4
H,
HH
O,
0
0
6
2 CF 3 COOH
acetone
/P
H
H
o-Q
P
- 2[PPN][CF 3COO]
\
0
00
E""""=
..
0~-.....
-- P
P P0
0
,
0-
A
"H-O-P
1/n
___1i
00
S
,
-
H..1
0
P
O-H'""
I
I
.0o
0
H-0
....
H
HJ
H
- n
Scheme 1.6: Synthesis of [PPN 2 1P 6 01 8 H 2 (H 3 0) 2 from [PPN]4[P6 0 1 sH 2 ] .2H 9 0 and
TFA. Hydrogen bonds are shown in dashed, and strong hydrogen bonds in thick
(lashed lines.
6 has a limited solubility in MeCN and acetone, which is speculated to be the consequence of intermolecular hydrogen bonds linking the anions into polymeric structure. The compound is soluble in hot MeCN (60 'C), which also supports the polyreric structure formed by intermolecular hydrogen bonds.
1.3.7
Structures of Metaphosphate Acids and Hydrogen Bonding
[PPNI 2 [P 3 0 9H] crystallizes in P2 1 space group. The crystal structure of 1 indicates
an intramolecular hydrogen bond between two phosphate units (Fig. 1-2). Significant
P-0 bond elongation was observed upon protonation, with a P1 -011 bond distance
of 1.5623
A,
A,
and shortening of the adjacent P1-012 bond to a distance of 1.4580
which is consistent with a P=0 double bond. Unprotonated P3-031,32 bond
distances are 1.4765 and 1.4741
A,
respectively. The P2-021 bond acting as a hy-
A, concomittant with the slight shortening
A, indicating partial localization of negative
drogen bond acceptor elongates to 1.4986
of the adjacent P2-022 bond to 1.4656
charge on the P-0 hydrogen bond acceptor. The 0... 0 hydrogen bond distance is
2.613
A.
[PPN] 2 [P 4 0 1 2 H 2 ] crystallizes in Pbca space group.
The crystal structure of 2
features two intramolecular hydrogen bond within the tetramnetaphosphate ring (Fig.
1-3). A crystallographic inversion center is located at the center of the tetrametaphos24
031
-
011
03
P2P
032
022
1
012
Figure 1-2: Solid-state structure of 1 with thermal ellipsoids at the 50% probability
level. IPPNJ+ cations are omitted for clarity.
phate ring and generates the whole anion from half of the ring in the asymmetric unit.
Similar elongation of the P-O bonds acting as hydrogen bond acceptors is observed
with P-O bond distances of 1.497
P-O bonds to 1.451
A,
together with slight shortening of the adjacent
. The hydrogen bond distances are 2.731
A.
Figure 1-3: Solid-state structure of 2 with thermal ellipsoids at the 50% probability
level. [PPNJ+ cations are omitted for clarity.
[PPN]4[(P 401 2 ) 3 Hs] crystallizes in P1 space group. The crystal structure of 3 in-
dicates a tris(tetrametaphosphate) complex, linked by eight intermolecular hydrogen
bonds into a three-decker structure (Fig. 1-4). A crystallographic inversion center
lies at the center of the middle tetrametaphosphate ring. Average hydrogen bond
distance is 2.463
A with
values ranging from 2.398 to 2.540 A, and can be classified
as Low-Barrier Hydrogen Bond (LBHB).
13
The terminal P-O bond distances of the
inner metaphosphate ring are in the range of 1.468 to 1.483
25
A,
suggesting a formally
[P 4 012 1 4
tetraanion with delocalization of the negative charges. The two outer rings
have distinctly different P-O bond distances: P-OH bonds involved in intermolecular hydrogen bonding range from 1.492 to 1.525
A, indicating
single bond character,
A,
consistent with double
while the external P=O bonds range from 1.443 to 1.456
bonds.
Figure 1-4: Solid-state structure of 3 with thermal ellipsoids at the 50% probability
level. [PPNJ+ cations are omitted for clarity.
As opposed to 1 and 2 of which hydrogen bonds are intramolecular, hydrogen
bonds in 3 are all intermolecular. Protonation of a P -0- unit decreases the electron
density available to the adjacent P=O unit, thus lowering the hydrogen bond accepting ability through an anti-cooperative effect.14 As a result, each tetrametaphosphate ring can only accommodate two protons with strong intramolecular hydrogen
bonds. If further protonation occurs, the extra proton cannot be stabilized by ionic
intramolecular hydrogen bonds, and oligomerization of metaphosphates will occur
as seen in 3. The three-decker complex can be viewed as two tetrametaphosphoric
acids stabilized by intermolecular hydrogen bonds to a tetrametaphosphate tetraanion. The middle tetraanion supplies sufficient negative charge to form strong ionic
hydrogen bonds with the rings above and below. It should be noted, however, that
26
all hydrogen bonds are LBHB and the proton exchange is dynamic, thus the inner
phosphate ring would be in a partially protonated state, while the two outer rings
would be in a partially ionized state.
Low-Barrier Hydrogen Bond is a special class of hydrogen bond which only occurs
in certain circumstances.13 First, the geometry of the hydrogen bond has to be linear.
Second, the potential energy landscape needs to be symmetric. Third, the hydrogen
bond distance must be short enough to allow delocalization of the wavefunction.
Metaphosphate acid 3 satisfies all requirements in this regard and could serve as a
platform to study LBHB in phosphate system. LBHB in phosphates is proposed to be
responsible for stabilization of transition states in enzymatic catalytic reactions.15,16
Dihydrogen hexametaphosphate has been synthesized before with 3,5-xylidinium
8
and 2-amino-5-chloropyridinium 1 2 cations. The previously reported structures feature the hexametaphosphate rings intermolecularly hydrogen-bonded to form a onedimensional network. The remaining unprotonated phosphate units accept hydrogen
bonds from the cations, making up three-dimensional structures.
The phosphate-
phosphate intermolecular hydrogen bonds are classified as LBHB, while hydrogen
bonds to the cations are normal hydrogen bonds.
IPPNI 4 IP 6 O1sH 2 ] .2H 20 crystallizes in P1 space group. Using
[PPNJ+ as counter-
cation, intramolecular hydrogen bonding in the hexametaphosphate was achieved, as
-
IPPN1+ cannot engage in classical hydrogen bonds. ' The crystal structure of IPPN] 4
[P 6 0 1 H 2 1-2H 2 0 shows the first monomeric dihydrogen hexametaphosphate with two
intramolecular hydrogen bonds (Fig. 1-5). The ring is found on a crystallographic
inversion center. The 021... 031' hydrogen bond distance is 2.409 A, and thus is
LBHB. Crystallization in MeCN/THF outside of the glovebox resulted in two water
molecules bound to the hexametaphosphate ring via normal hydrogen bonds, with
01w... 011 distance of 2.801 A for hydrogen bonding to the unprotonated phosphate
and 01w. - - 032' distance of 2.916 A for hydrogen bonding to the phosphate currently
involved in LBHB.
Crystallization of IPPN]3[P6 0
18H3 ] from
MeCN/DME produced block-shaped col-
orless crystals suitable for single crystal X-ray diffraction. The [P 6 0 18 H 313- anion
27
P1
01w
P3
O1wi
21
P3i
032i
*
P2
031i
PPli
Figure 1-5: Solid-state structure of 4 with thermal ellipsoids at the 50% probability
level. IPPN1+ cations are omitted for clarity.
crystallized in P1 space group as a monomer with three IPPN] + cations in the asymmetric unit. Three LBHBs are present in the metaphosphate, with
of 2.4195, 2.4208, and 2.442
o ... o
distances
(Fig. 1-6).
Figure 1-6: Solid-state structure of 5 with thermal ellipsoids at the 50% probability
level. IPPNI+ cations are omitted for clarity.
Vapor diffusion of Et 2 0
into MeCN solution of [PPNI 2 [P6 Oi 8 H 2 (H 3 0)21 gave
block-shaped colorless crystals. Single crystal X-ray diffraction showed that 6 crystallized into a one-dimensional network of intermolecularly, doubly hydrogen-bonded
hexametaphosphate chain (Fig. 1-7). The hydrogen bonds are classified as LBHB
with the distances of 2.465
A. A crystallographic
inversion center generates the hexam-
etaphosphate ring. Two water molecules are found bound to the hexametaphosphate,
28
each of which is stabilized by three hydrogen bonds to the metaphosphate. Two of the
hydrogen bonds are normal hydrogen bonds with Olw... 021,31 distances of 2.596
and 2.629
A,
belonging to hydrogen bonds from the water molecule to the phosphate.
The third hydrogen bond is LBHB, with 01w.. 011 distance of 2.449 A. The position of the hydrogen atom is computationally found to be on the oxygen atom of
the water molecule (Appendix B), effectively characterizing the adduct as hydronium
ions on the hexametaphosphate anion.
01w
031
P3
1
032
P1i
022
P2
P
012
P31
021
Figure 1-7: Solid-state structure of 6 showing the monomeric unit (L) and polymeric
structure (R), with thermal ellipsoids at the 50% probability level. [PPN+ cations
are omitted for clarity.
[PPN 2 [P6 O 1sH 2 (H 3 0) 21 is the second class of single-molecule adduct with hydro-
nium ion structurally characterized in a pseudo-C3 environment. Polyethers are the
first compound found to make adducts with hydronium ion,
17,18
but 6 is the first
anionic single molecule to encapsulate hydronium ions. Since the basicity of an anion
is enhanced in organic media compared to in aqueous media,19 the fact that hexametaphosphate is not protonated by the hydronium ion demonstrates the remarkably
weak basicity of the hexametaphosphate supporting framework.
1.4
Conclusions
The new methodology developed herein has enabled the synthesis and characterizations of metaphosphate acids. Metaphosphate acids are prepared in high yields
29
and isolated in high purity from MeCN or acetone solution.
The acid chemistry of
metaphosphate, which was previously elusive due to the leveling effect of strong acids
in water, has been studied to great details. Strong ionic hydrogen bonds are the main
feature of these acids. It is proposed that, in aprotic solvents, due to the preference
for metaphosphate acids to form ionic hydrogen bonds, anti-cooperative effect would
dictate the acids to be monomeric when the degree of protonation is less than or equal
to half the number of phosphate units, and oligomeric or polymeric when the degree of
protonation is more than half the number of phosphate units. The synthetic methodology described for metaphosphate acids are also believed to be applicable to other
oxoanionic systems such as polyoxometalates and silicates. Metaphosphate acids represent a new class of compound which will potentially find their various uses as new
strong polyprotic acids available in solid form. Applications in the synthesis of metal
metaphosphate complexes via protonolysis have been explored,
2
and more uses in
diverse areas including biological phosphorylating agent (Chapter 2), acid catalysis,
proton transport,
1.5
22
and ferroelectric materials
23
2
are the possibilities.
Experimental Details and Procedures
General Methods
All operations were performed either in a Vacuum Atmospheres drybox under an
[P 3 0 91 H 2 0,2 4 [PPN]4[P 4 0 12 -5H 2 0,
published procedures.
25
and Li6
2
i[P1 1
6 0 18
[PPN] 3
-
atmosphere of purified nitrogen or in a fume hood under air atmosphere.
were prepared according to
IPPNICl was purchased from BOC SCIENCES and used as
received. TFA 99% was purchased from Sigma Aldrich and used as received. TFAA
and TfOH were purchased from Oakwood Chemicals and used as received. Reagent
grade acetone was purchased from Macron Fine Chemicals and used as received.
Reagent grade Et 2 0 was purchased from Fischer Scientific and used as received.
Deionized water was purchased from Ricca Chemical Company, USA (p > 18 MQcm).
Dry MeCN, THF, DME, and pentane were dried and deoxygenated by the method of
30
Grubbs using a system built by SG Water USA, LLC and stored over 4
sieves.
4
A
A molecular
molecular sieves were dried under reduced pressure at a temperature
above 200 'C over the course of one week. Deuterated acetonitrile was obtained from
Cambridge Isotope Laboratories and dried over 4
and
31
A
molecular sieves prior to use.
1
H
P{ 1 H} NMR spectra were recorded on Varian Mercury-300 or Bruker AVANCE-
400 spectrometers.
'H NMR chemical shifts are reported with respect to internal
solvent residual (CD 3 CN, 6: 1.94 pprm).
31
P NMR chemical shifts are reported with
respect to an external reference (85% H 3 PO 4 , 6: 0.00 ppm).
13
C NMR chemical
shifts are reported with respect to internal solvent residual (CH 3 CN, 6: 118.26 ppm).
Infrared spectra were recorded on a Bruker TENSOR37 FT-IR Spectrophotometer.
Elemiental analyses were performed by Robertson Microlit Laboratories, Inc.
Preparation of [PPN]2[P 3 0 9 H]-THF (1-THF)
Inside a glovebox, to a solution of [PPNI 3 [P 3O 9 j-H 2 0 (0.5631 g, 0.301 inmiol, 1.0
equiv) in MeCN (3 mL) was added a solution of TFA (0.301 mmol, 1.0 equiv) in
MeCN (0.5 mL). The reaction mixture was stirred for 5 mmi, and THF (100 nL)
was added until the solution became cloudy white. The product crystallized out as
block-shaped colorless crystals. The crystals were isolated on a fine porosity fritted
funnel, washed with THF (3 x 10 irmL), and dried under reduced pressure to afford the
product as white solid (0.3170 g, 0.241 mmniol, 80.1% yield).
Elem. Anal. Found: C, 64.95; H, 5.05; N, 1.99%. Calc. for C 76 H69 N 2
1O
0 P7 :
C,
65.80; H, 5.01; N, 2.02%. 'H NMR (CD 3 CN, 400 MHz, ppm): 6 12.55 (br, 1 H, OH),
7.4-7.8 (m, 60 H, HAr), 3.63 (m, 4 H, OCH2), 1.79 (in, 4 H, OCH 2 CH2 ).
31
p{ 1 H}
NMR (CD 3 CN, 162 MHz, ppm): 6 22.20 (s, 4 P, IPPNI+), -20.43 (br, 3 P). 13C NMR
(CH 3 CN, 100 MHz, ppm) 6 134.57 (s), 133.17 (in), 130.33 (in), 128.14 (d, iJpc=108
Hz). IR (ATR, cimv 1): v 1250 (s), 1111 (s), 985 (s).
31
Preparation of [PPN]2[P 4 01 2 H 2] (2)
In a fume hood, IPPN]4IP 4O12].5H 2 0 (4.227 g, 1.670 mmol, 1.0 equiv) was suspended
in acetone (40 mL). To this stirring suspension was added dropwise a solution of
TFAA (240 tL, 1.700
imol, 1.02 equiv) in acetone (10 niL). The suspension turned
into colorless homogeneous solution, before white precipitate began to crash out of
the reaction mixture after complete addition. The reaction mixture was stirred for 40
min to allow complete precipitation of 2. The solid was then collected by filtration on
a medium porosity fritted funnel, washed with acetone (10 nL), and dried in vacuo,
affording 2 as a white solid (2.194 g, 1.572 umol, 94% yield).
Elemn. Anal. Found: C, 61.95; H, 4.64; N, 2.04%. Calc. for C 72 H 6 2 N 2 0 12 P8 : C,
61.99; H, 4.48; N, 2.01%.
7.4-7.8 (in, 60 H, HAr).
[PPNJ+), -25.60
1H
31
NMR (CD 3CN, 300 MHz, ppi) J 14.03 (br, 2 H, OH),
p{'H} NMR (CD 3 CN, 121.5 MHz, ppm) 3 22.10 (s, 4 P,
(br, 4 P).
13 C
NMR (CD 3 CN, 75 MHz, ppmn) 3 133.62 (s), 132.26
(mu), 129.39 (im), 127.24 (d, 1Jpc=107 Hz). ESI-MS(-)(CH 3CN, m/z): 318.8122
([P 4 01 2 H2]2-+H+), 158.8814 ([P 4 0 12 H 2 I2 -). IR (ATR, cm- 1):
v 1270 (s), 1022 (s),
996 (s).
Preparation of [PPN] 4 [(P 4 0
12 ) 3H81DME
(3-DME)
Inside a glovebox, to a suspension of [PPN1 2 1P 4 0 1 2 H 2 ] (0.4996 g, 0.358 mumol, 1.0
equiv) in MeCN (2.5 nL) was added 2.60 mL TfOH solution in MeCN (0.137 M,
0.357 minol, 1.0 equiv). Upon the addition, the suspension turned into homogeneous
colorless solution. The reaction mixture was stirred for 5 min, and then was added
to stirring DME (100 mL) to crash out the product as white solid. The solid product
was isolated on a medium porosity fritted funnel, washed with DME (3 x 10 iL),
pentane (3x3 nL), and dried under reduced pressure to afford the product as white
solid (0.2710 g, 0.0847 miol, 71.0% yield).
Elen. Anal. Found: C, 54.71; H, 4.25, N, 1.85%. Calc. for C14sHl 3sN 4 038P 2 0: C,
55.55; H, 4.35; N, 1.75%.
1H
NMR (CD 3 CN, 300 MHz, ppm): J 13.73 (br, 8 H, OH),
7.4-7.8 (in, 120 H, HAr), 3.45 (s, 4 H, OCH2 ), 3.28 (s, 6 H, OCH3 ).
32
31 P{1 H}
NMR
(CH 3 CN, 121.5 MHz, ppm): 6 22.27 (s, 8 P, IPPN]+), -30.06 (br, 12 P).
13
C NMR
(CH 3 CN, 100 MHz, ppm) 6 134.55 (s), 133.19 (m), 130.32 (m), 128.16 (d, 1 Jpc=107
Hz), 72.39 (s, DME), 58.80 (s, DME). IR (ATR, crrm
1 ):
v 1249 (s), 1110 (s), 1024
(s), 994 (s).
Preparation of [PPN]4[P 6 0 18 H 2 ]-2H 2 0
(4)
Li 6 P 6 OisI was purified frorm polyphosphate impurities by agitating Li4[P6 OisI in
deionized water for 15 mini, filtering through medium porosity fritted funnel, and removing volatiles from the filtrate under a rotary evaporator. In a fume hood, [PPNCL
(17.82 g, 31.0 mmnol, 4.0 equiv) was dissolved in deionized water (500 mL) heated at
60 'C, and the solution was cooled down to 45 'C. To the stirring, warm solution of
[PPNC was added a solution of Li 6 fP 6 OisJ (4.03 g, 7.82 mnmol, 1.0 equiv) in deionized water (50 mL), resulting in precipitation of white solid. The reaction mixture
was stirred at 45 'C for 45 min, and then was cooled down to room temperature.
The product was isolated on a medium porosity fritted funnel, washed with deionized
water (3 x 40 nL), and dried under reduced pressure at 40 'C for 17 Ii to yield white
solid material (19.02 g).
The isolated material was a partially protonated hexam-
etaphosphate [PPN] 6 -_[P6 OisHx1 which was converted into [PPN]4[P 6 Oi 8 H 2 2H 20
upon thermal treatment during drying process. A portion of the isolated material
(8.0213 g) was purified by crystallization from MeCN/THF (30 mL/400 miL). Colorless crystals were isolated on a imedium porosity fritted funnel, washed with THF
(3 x 30 mL), and dried under reduced pressure at 60 'C for 4 h to afford the desired
product (6.3532 g, 2.178 mmol, 66.0% overall yield).
Elem. Anal. Found: C, 64.11; H, 4.72; N, 2.11%. Calc. for C 144 H 12 6 N 4 0 2 0 P1 4: C,
64.87; H, 4.76; N, 2.10%. 1H NMR (CD 3CN, 300 MHz, ppm): 6 12.53 (br, 2 H, 01),
7.4-7.8 (m, 120 H, HAr).
31
[PPN1+), -24.95 (br, 6 P).
P{ 1H} NMR (CH 3CN, 121.5 MHz, ppm): J 22.22 (s, 8 P,
13
C NMR (CH 3 CN, 100 MHz, ppm) 6 134.56 (s), 133.13
(im), 130.24 (m), 128.10 (d, 1 Jpc=108 Hz). IR (ATR,
1112 (s), 996 (s), 948 (s).
33
cm- 1): v 1287 (m), 1233 (s),
Preparation of [PPN]3[P6 Oi 8 H 3]-DME (5-DME)
Inside a glovebox, [PPNI 4 [P6 OisH 2I-2H 20 (0.5005 g, 0.188 mirol, 1.0 equiv) was
dissolved in MeCN (3 rL). To this solution was added a solution of TFA (19 pL,
0.256 ininol, 1.36 equiv) in MeCN (1 rnL). The reaction mixture was stirred for 3
min, and then was added dropwise to a stirring DME (80 miL). The product crashed
out as white precipitate. The solid was collected on a medium porosity fritted funnel,
washed with DME (3 x 10 nL), and dried under reduced pressure to afford the desired
product as white powder (0.3590 g, 0.164 irimol, 87.6% yield).
Elen. Anal. Found: C, 60.37; H, 4.84; N, 2.03%. Calc. for C11 2 H1
0 3N 30 20 P1 2 :
C,
61.63; H, 4.76; N, 1.93%. 'H NMR (CD 3CN, 300 MHz, ppm): 6 15.20 (br, 3 H, O),
7.4-7.8 (in, 90 H, HAr), 3.45 (s, 4 H, OCH 2 ), 3.28 (s, 6 H, OCH3 ).
31 p{ 1 H}
(CD 3 CN, 121.5 MHz, ppm): 6 22.24 (s, 6 P, [PPNI+), -28.09 (br, 6 P).
13C
NMR
NMR
(CH 3 CN, 100 MHz, ppm) 6 134.56 (s), 133.19 (in), 130.33 (m), 128.16 (d, 1 Jpcz=108
Hz). IR (ATR, dne 1 ): v 1239 (s), 1112 (s), 1064 (s), 1023 (s), 996 (s).
Preparation of [PPN] 2 [P6 0isH 2 (H 3 0) 2] (6)
In a fune hood, [PPN] 4 [P6 0 18 H 212H 2 0 (0.2010 g, 0.075 inmol, 1.0 equiv) was suspended in acetone (1 muL). To the stirring suspension was added a solution of TFA
(13 jtL, 0.175 mnmol, 2.32 equiv) in acetone (0.5 mL). The suspension turned into
colorless homogeneous solution upon complete addition, and white solid started to
precipitate out after 30 s. The reaction mixture was allowed to stir for 2 h. The solid
product was isolated on a mnedium porosity fritted funnel, washed with acetone (2 x3
mnL), and dried under reduced pressure to afford the product as white powder (0.0908
g, 0.057 mmnol, 75.7% yield).
Elemn. Anal. Found: C, 54.61; H, 4.11; N, 1.69%. Calc. for C 72 H 68 N 2 0 2 0 Pio: C,
54.35; H, 4.31; N, 1.76%. 'H NMR (CD 3 CN, 300 MHz, ppm): 6 13.48 (br, 4 H, O),
7.4-7.8 (i, 60 H, HAr).
31
p{'H} NMR (CH 3 CN, 121.5 MHz, ppm): 6 22.26 (s, 4 P,
[PPNJ+), -27.34 (br, 6 P).
13C
NMR (CH 3 CN, 100 MHz, ppm) 6 134.55 (s), 133.18
(m), 130.32 (in), 128.16 (d, 'Jpc=108 Hz). IR (ATR, cmir-1): v 1228 (s), 1113 (s),
34
1074 (s), 884 (br, s).
X-ray Data Collection and Structure Determinations
Single crystal X-ray diffraction data for 1-6 (0- and w-scans) were collected at 100
K on a Bruker-AXS X8 Kappa Duo diffractometer coupled to a Smart Apex2 CCD
detector, using graphite-mnonochromated Mo-Ka radiation (A = 0.71073
cessed through the SAINT1 7 reduction and SADABS
28
structures were solved by direct methods using SHELXS
29
A), aid pro-
absorption software.
The
aid refined against F2 on
all data by full-matrix least squares with SHELXL-2013, " using established methods.
31 3 2
,
All non-hydrogen atoirs were refined anisotropically. The hydrogen atoms
on the phenyl rings of the [PPNJ+ cations and those on solvent molecules were generally included at geometrically calculated positions and refined using a riding model.
Crystal data and refinement conditions for 1-6 are summarized in Tables 1.1-1.3.
Colorless crystals of [PPNI 2 [P3 0 9 H] were grown from vapor diffusion of THF into
a concentrated solution of [PPN] 2 [P 3 0 9 H] in MeCN inside a glovebox using dry solvents.
1 crystallizes in the monoclinic space group P2 1 with one THF molecule in
the asymmetric unit. One phenyl ring of [PPNj+ cation was found to be partially
disordered, which was treated with rigid group refinements (AFIX 66). The carbon
atoms C21b/C221 and C22b/C222 on the phenyl ring were constrained using EADP
to have the samie positional aid displacement parameters as needed to stabilize the
refinement. The hydrogen atom on the P-OH moiety was placed in calculated position aid refined as riding atom. The P-OH moiety could be easily identified on the
basis of the P-O bond length (P1-011, 1.562 A vs P2-021, 1.499 A aid P3-031,
1.477
A);
a reasonable intramolecular hydrogen bond could be identified, supporting
the correct placemnent of the hydroxyl hydrogen atom (021- - -011, 2.613
A).
Colorless crystals of [PPN]2[P 4 0 12 H 2 ] were grown in situ from the reaction of
[PPN]4[P 40 12 I-5H 20 with TFAA in acetone outside of the glovebox using unpurified solvent.
[P 4 012H 2 ]2
2 crystallizes in the orthorhombic space group Pbca, with half of the
anion in the asymmetric unit, along with a [PPNJ+ countercation. The
dillydrogen tetrametaphosphate anion was found to be disordered. All the oxygen
35
atoms were modeled over two positions, which were refined freely within SHELXL
while constraining the sun of the occupancies to unity; the relative occupancies of
the two alternative sets reached values of 0.58 : 0.42 at convergence.
The disorder
was treated with the aid of similarity restraints on the 1,2- and 1,3- distances, as well
as rigid bond restraints. 33 The hydrogen atoms on the P-OH moieties were placed in
calculated positions by referring to a good distance from neighboring P =0 acceptors
and refined as riding atoms.
Colorless crystals of [PPN]4[(P 4 01 2 ) 3 H8 ] were grown from a mixture of MeCN
arid DME inside a glovebox using dry solvents. 3 crystallizes in the triclinic space
group P1 with one DME molecule in the asymmetric unit. One tetrametaphosphate
ring was found to be disordered. Three phosphorous atoms and all the oxygen atoms
were modeled over two positions, which were refined freely within SHELXL while
constraining the surl of the occupancies to unity; the relative occupancies of the two
alternative sets reached value of 0.83 : 0.17 at convergence. The disorder was treated
with the aid of similarity restraints on the 1,2- (P -0) and 1,3- (0.
well as rigid bond restraints.
3
. .
0) distances, as
All the hydrogen atoms on the P-OH moieties were
found from the difference Fourier synthesis, and were restrained using DFIX.
Colorless crystals of [PPN] 4 [P6 0 18 H 2 ] 2(H 2 0)(THF)1.412(MeCN )0.587 were grown
from a mixture of MeCN and THF outside of a glovebox using unpurified solvents.
4.(THF)1412(MeCN) 0 5. 8 7 crystallizes in the triclinic space group P1 with 1.41 THF
molecules and 0.59 MeCN molecules in the asymmetric unit.
One phenyl ring of
{PPNj+ cations was found to be partially disordered, which was treated with rigid
group refinements (AFIX 66). One partially occupied MeCN molecule and one partially occupied THF molecule could be refined freely with SHELXL. The partially
occupied MeCN molecule were refined by restraining the 1,2- (C -C, C-N) and 1,3(C... N) distances to the target values. Geometrical restraints were applied to the
THF molecule; in particular, 1,2- (C-C, C-0) and 1,3- (C- - - C, C.. -0) distances
were refined by restraining their lengths to the targeted values. The hydrogen atoms
of water molecule and the P-OH moieties were found from the difference Fourier
synthesis, and were restrained using DFIX.
36
Colorless crystals of IPPN 3 IP6 O 1 sH 3 ] were grown from a mixture of MeCN and
DME inside a glovebox.
5 crystallizes in the triclinic space group P1 with three
[PPNJ+ cations and one [P 6 0 1 8 H 313- anion in the asymmetric unit. Some bridging
and terininal oxygen atoms of the hexametaphosphate ring were found to be disordered, and were modeled over two positions. The relative occupancies were refined
freely within SHELXL and converged to the relative occupancies of 0.85 : 0.15. The
disorder was treated with the aid of similarity restraints on the 1,2- (P -0) distances.
Similar anisotropic displacement parameters were applied to the minor disordered
component to stabilize the refinement. Tle hydrogen atoms on the hexametaphospliate ring were found from the difference Fourier synthesis, were restrained using
DFIX frorm the oxygen atoms, and were stabilized by similarity restraints on the 1,3(P... H) distances. There appears to be two disordered DME miolecules in solvent
as implemented in Platon
35
The program Squeeze
"
accessible voids, and as supported by 'H NMR spectrum.
was used to remove the contribution of the disordered
solvent from the diffraction data.
Colorless crystals of [PPN]2[P 6 OisH 2 (H 3 0)21 were grown from vapor diffusion of
Et 2 0 into MeCN solution outside of the glovebox using unpurified solvents. 6 crystallizes in the rmonoclinic space group P21/n with one [PPNI+ cation and half hexametaphosphiate ring in the asymmetric unit. The crystallographic inversion center
lies at the center of the hexametaphosphate ring and generates the other half of the
ring.
Some bridging oxygen atomis of the hexametaphosphate ring were found to
be disordered, and were modeled over two positions. The relative occupancies were
refined freely within SHELXL and converged to relative occupancies of 0.68 : 0.32.
Similarity restraints on displacement paramiieters and rigid bond restraints were applied.
The hydrogen atoms on the hexametaphosphate ring were found from
the
difference Fourier synthesis, and were restrained using DFIX from the oxygen atoms.
Two residual electron peaks were found between the 01w... 011, where the hydrogen
bond distance is 2.449
A
consistent with LBHB. The hydrogen atomn was placed on
01w, as suggested by DFT calculation (Appendix B).
37
)
Reciprocal Net code / CCDC No.
Empirical formula, FW (g/nol)
Crystal size (mm 3
Temperature (K)
Wavelength (A)
Crystal system, Space group
a (A), c( 0)
b (A), /(0)
C(A), ()
Volume (A3)
Z
)
Density (calc., g/cm 3
Absorption coefficient (mm')
F(000)
Theta range for data collection (0)
00
Index ranges
Reflections collected
Independent reflections, Rj
Completeness to 0 = 25.242'
Refinement method
Data / restraints / parameters
Goodness-of-fit on P
Final R indices [I > 2-(J)I
R indices (all data)
Extinction coefficient
Largest diff. peak and hole (e-A-3)
[PPN]2[P 3 09 H] (1)
X8_ 14028 / 1062925
C7 6 H 69 N 2 0 10 P 7, 1387.12
0.30 x 0.29 x 0.26
100(2)
0.71073
Monoclinic, P2 1
10.5931(13), 90
25.176(3), 102.843(2)
12.9215(15), 90
3359.8(7)
2
1.371
0.247
1448
1.616 to 31.529
-14<h<15
-36<k<37
-18<1<18
113001
21387 (0.0273)
100.0%
Full-matrix least-squares on P
[PPN] 2 [P4 0 12H2 ] (2)
X8_13135 / 998201
C 72 H6 2 N 2 0 12 P8 , 1395.00
0.50 x 0.40 x 0.30
100(2)
0.71073
Orthorhombic, Pbca
19.9148(9), 90
16.3924(7), 90
19.9502(9), 90
6512.8(5)
4
1.423
0.281
2896
1.906 to 30.579
-26<h<28
-17<k<23
-28<1<26
75134
9957 (0.0383)
100.0%
Full-matrix least-squares on P
21387 / 1600 / 876
9957 / 256 / 481
1.043
R, = 0.0343, wR 2 = 0.0894
R1 = 0.0359, wR 2=0.0906
n/a
0.825 and -0.516
1.036
R, = 0.0373, wR 2 = 0.0971
R1 = 0.0467, wR 2 = 0.1040
n/a
0.556 and -0.540
Table 1.1: Crystallographic data for [PPN] 2 [P 30 9 H] and [PPN]2[P 4 0 12 H 2 ]
Reciprocal Net code / CCDC No.
Empirical formula, FW (g/mol)
C 14 8 H 13sN 4 0 38 P 2 0, 3200.02
0.59 x 0.17 x 0.06
100(2)
0.71073
Triclinic, Pl
17.841(3), 82.161(3)
)
Crystal size (mm 3
Temperature (K)
Wavelength (A)
Crystal system, Space group
a (A), a (0)
b (A), 3(0)
C (A), -Y (0)
Volume (As)
Z
17.919(3), 72.116(3)
26.667(4), 63.234(2)
7244.0(19)
2
1.467
)
Density (calc., g/cm 3
Absorption coefficient (mm-
[PPN] 4 [(P 4 0 12 )3 H8 ] (3)
X8_14115 / 1062926
0.312
)
1
F(000)
Theta range for data collection
Index ranges
(0)
Reflections collected
Independent reflections, Ri
Completeness to 6 = 25.242'
Refinement method
Data / restraints / parameters
Goodness-of-fit on T2
Final R indices [I > 2r(1)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole (e.A-3)
3316
1.273 to 29.575
-24<h<24'
-24<k<24
-37<1<37
193547
39780 (0.0714)
98.7%
Full-matrix least-squares on F2
39780 / 3611 / 2054
1.025
R1 = 0.0546, wR 2 = 0.1280
R, - 0.1096, wR 2 = 0.1562
n/a
0.750 and -0.655
[PPN]4[P6 0 1 8 H 2].2H 2 0 (4)
X8_14137 / 1062927
C 15 7.6 5 H15 2.13 N 5 .170 22.83P 14
0.42 x 0.16 x 0.13
100(2)
0.71073
Triclinic, Pi
14.7633(9), 97.0320(14)
16.1312(10), 107.0490(13)
17.2418(11), 109.7810(13)
3580.2(4)
1
1.353
0.237
1527
1.275 to 31.028
-20<h<21
-23<k<22
-25<1<24
132624
22571 (0.0425)
99.7%
Full-matrix least-squares on
22571 / 161 / 978
1.048
R, = 0.0514, wR 2 = 0.1291
R, = 0.0745, wR 2 = 0.1422
n/a
1.258 and -0.772
Table 1.2: Crystallographic data for [PPN]4[(P 4 0 12 ) 3H 8 ] and [PPN] 4 [P6O 18 H 2j-2H20
)
Reciprocal Net code / CCDC No.
Empirical formula, FW (g/mol)
Crystal size (mm 3
Temperature (K)
Wavelength (A)
Crystal system, Space group
a (A), c(0)
b (A), 3(0)
C (A), 1(0)
[PPN] 2 [P6 0 1 8 H 2 (H 3 0)21 (6)
X8_14164 / 1062929
C 5 4 H 46 .5 0N 1. 50 0 9P 6 , 1046.24
C 72 H 6 8N 2 0 20 P1 0 , 1590.98
0.34 x 0.26 x 0.14
100(2)
0.71073
0.27 x 0.18 x 0.14
100(2)
0.71073
Triclinic, P1
13.1896(14), 87.387(3)
17.2310(17), 75.190(3)
24.240(3), 72.054(3)
5063.6(9)
4
1.372
Monoclinic, P2 1 /n
8.8015(4), 90
30.5879(12), 105.5100(10)
13.6623(6), 90
3544.3(3)
2
)
Volume (As)
Z
Density (calc., g/cm 3
Absorption coefficient (mm-1)
[PPN 3 [P6 01H 3 ] (5)
X8_ 15018 / 1062928
0.271
2172
F(000)
Theta range for data collection
(0)
Index ranges
1.243 to 30.106
-18<h<18
-24<k<24
-34<1<34
Reflections collected
Independent reflections, Rit
Completeness to 0 = 25.2420
Refinement method
Data / restraints / parameters
Goodness-of-fit on P
Final R indices [I > 2o-()]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole (e.A-3)
1.491
0.319
1648
1.331 to 32.574
-13<h<13
-46<k<46
225518
29640 (0.0347)
100.0%
-20<1<20
138841
12913 (0.0317)
100.0%
Full-matrix least-squares on F2
Full-matrix least-squares on F2
29640 / 28 / 1305
1.029
12913 / 811 / 501
1.033
R, = 0.0345, wR 2 = 0.0955
R, = 0.0391, wR 2 = 0.0989
R, - 0.0400, wR 2 - 0.1037
R, = 0.0478, wR 2 =0.1097
n/a
0.845 and -0.929
n/a
0.563 and -0.738
Table 1.3: Crystallographic data for [PPN] 3 [P6 0 1 8H 3] and [PPN]2[P 6 0 18 H 2 (H 3 0)21
Chapter 2
Synthesis of Metaphosphate
Anhydrides and Alcoholysis
Reactions
2.1
Introduction
Condensation of orthophosphoric acid is known to yield a mixture of ultraphosphates,
which subsequently gives off a complete series of inetaphosphates ranging from tri- to
decametaphosphate upon hydrolysis. Tetrametaphosphate was the major species in
this hydrolyzed mixture, constituting 75% of the total phosphate. " Ultraphosphates
are defined as phosphates with a composition ratio of M 2 0/P2 05
<
1.0, where M is
one equivalent of a cation or a single function of a covalently bonded moiety such as an
alkyl group.37,38 Ultraphosphates usually exist in poorly-defined polymeric structures;
however, all evidence by
31
P NMR suggested the existence of a small molecular ultra-
phosphate. The small ultraphosphate was produced in a mixture of ultraphosphates
from the condensation of orthophosphoric acid with carbodiimide in tetramnethylurea
solution, and was proposed to be 1,5-p-oxo-tetramrietaphosphate. 37
The presence of 1,5-/-oxo-tetrametaphosphate in the ultraphosphate mixtures explained the hydrolysis reaction which gave off tetramnetaphosphate as the major prod-
41
uct. The reaction of 1,5-p-oxo-tetrarnetaphosphate with one equivalent of water would
produce dihydrogen tetraimetaphosphate (Scheme 2.1) via hydrolytic cleavage at the
thermodynamically unstable branched phosphate unit (the phosphate unit with three
oxygen shared with neighboring phosphates). 38 The reaction is reversible; the reverse
reaction, dehydration of metaphosphate acid, is achievable by the use of dehydrating
agents such as trichloroacetonitrile.3
\0
\\ /0
/
O==FP
o
o
-
0O
H 20
HO
H2 0
0
/
\
0
/
OH
/
qoP==:O
0
dihydrogen tetrametaphosphate
1,5-g-oxo-tetrametaphosphate
Scheme 2.1: Hydrolysis of 1,5-p-oxo-tetrametaphiosphiate with one equivalent of water
The small ultraphosphate has not been isolated and purified from the mixture of
polymeric ultraphosphates. As a result, little is known about its properties and reactivity. The problem is associated with the condensation reaction of orthophosphoric
acid which gives a mixture of ultraphosphates that is difficult to purify. With available metaphosphate acids in hand, we were curious to see if dehydration reaction of
metaphosphate acids would yield well-defined ultraphosphates. Since ultraphosphates
are defined as cross-linked polymer of phosphates,
36,37,39
and since the dehydration
reaction of metaphosphate acid resembles the synthesis of acid anhydride from carboxylic acid, the molecular dehydration product of metaphosphate acid are thereby
defined as rmetaphosphate anhydride.
42
2.2
Results and Discussion
2.2.1
Synthesis of [PPN] 2 [P 4 01 1J (7)
Carbodiimide is a common dehydrating agent for phosphates, as implemented in the
synthesis of nucleotide." Condensation of orthophosphoric acid with carbodiimide
also showed the generation of tetrametaphosphate anhydride in tetramethylurea solution. 3 7 Treatment of N,N'-dicyclohexylcarbodiimide (DCC) with [PPN]2[P 4 01 2 H 2 ]
in MeCN solution produced 7 quantitatively, and it was isolated in 92% yield (Scheme
2.2). The reaction is accompanied by the formation of white solid consistent with the
insoluble N,N'-dicyclohexylurea (DCU) byproduct, which was separated by filtration.
This synthesis presents the first clean isolation of tetrametaphosphate anhydride. The
31
P{ 1 H} NMR spectrum of 7 features two signals at 6 -24.40
-32.51 (t,
2
Jpp
(t,
2
Jpp =29 Hz) and
= 29 Hz) ppm, and is consistent with previous study.
37
(PPN') 2
(PPN+) 2
V
DCC, MeCN
-DCU
0
O;
0
-
o
H20, acetone
1
.
-
O/
O
0
0
H
Scheme 2.2: Synthesis of IPPN]2[P 4 0i] from dehydration of IPPN12IP 4 0 12H 2] and
the hydrolysis reverse reaction
Hydrolysis reaction of 7 was achieved by dissolving 7 in unpurified acetone containing <0.5 %w/w water content. Colorless block-shaped crystals of 2 began to form
after 1 h. After 48 h of crystallization, 2 was isolated as crystalline solid in 68% yield.
Crystals of IPPNI2[P 4 OuI were grown from vapor diffusion of Et 2 0 into MeCN
solution of 7. The structure of 7 was obtained from single crystal X-ray diffraction
experiment, corroborating the structural model proposed in 1970. 3
in P2 1 /c space group.
7 crystallizes
The eight-membered tetrametaphosphate ring is fused by
the phosphoanhydride bridge into two six-membered phosphate rings, one in a chair
43
...
.......
...
...
conformation and another in a boat conformation.
Figure 2-1: Solid-state structure of 7 with thermal ellipsoids at the 50% probability
level. IPPN]+ cations are omitted for clarity.
2.2.2
Alcoholysis of [PPN]2[P 4 011]
Hydrolysis of 7 gave 2 as the product. The phosphoanhydride bridge at the branched
phosphate units of 7 appeared to be reactive toward nucleophilic attack. Recent work
in the group has shown that treatment of 7 with methanol in MeCN solution resulted
in the nucleophilic attack of methanol at the phosphoanhydride bond (Scheme 2.3),
cleaving the tetrametaphosphate anhydride into methyl tetrametaphosphate ester
IPPN]2[P 4 010(OH)(OMe)] (9).20
CH 3
(PPN*) 2
0
0
50 MeOH
- :1
10
01:, -
(PPN+) 2
MeCN
\
d
0
0 I, '--0
-
0
/zz:
0
.I0k0,
-
Scheme 2.3: Synthesis of IPPNI 2 IP 4 0O(OH)(OMe)] from methanolysis of IPPN] 2
[P 4 0111
The alcoholysis of 7 has shown to be a selective way to make tetrametaphosphate
44
ester. Similar reaction between phosphorus (III/V) oxide and methanol also yielded
methyl phosphate esters, but the four phosphorus units were not preserved ill protic
solvent.41 Instead, methanolysis of 7 in aprotic solvent maintains the tetrametaphosphate structure over the transformation. In this regard, 7 serves as a phosphorylating
agent, attaching a tetrametaphosphate group onto an alcohol. Because of the prevalence of phosphorylating agent in biological molecules, 7 was tested with biologically
relevant alcohols.
Treatment of 7 with cholesterol in dichloromethane (DCM) afforded a cholesteryl
hydrogentetrametaphosphate ester [PPN]2{P 4 0 1o(OH)(R)I (10), where R = cholesteryl
(Scheme 2.4). The reaction was quantitative as indicated by
31
P{'H} NMR, and the
product was isolated in 86% yield.
(PPN*) 2
0
0
0-
-
H
H
HO,
(PPN*) 2
0
0
O
DCM, 23*C
P-0H
6 days
0
0
\
- :I
|| _
0
__
0
Scheme 2.4: Synthesis of [PPN] 2 [P 4 01o(OH)(R)] from alcoliolysis of IPPN] 2 [P 4 01 1 1
by cholesterol
The
31
p{ 1 H} NMR (CH 2 Cl 2 ) spectrum of 10 features three signals corresponding
to the phosphate at 6 -23.29
Hz, 2 P), and -27.56
(t,
2
JpP
= 25 Hz, 1 P), -25.24
(t, 2 JpP = 25 Hz, 1 P) ppm.
3 1P
(dd,
3
Jpp
=
25, 28
NMR (CH 2 C 2) spectrum
features the peak at J -27.56 ppm split into a triplet of doublets with
and
2
2
JpP = 25 Hz
JHP = 7 Hz. 1H NMR (CDCl 3 ) spectrum of 10 features the signal of the acidic
proton at J 11.15 ppm (br, 1 H, P-OH) and the secondary alcohol hydrogen at J
4.44 (im, 1 H, 0-CH) ppm.
45
Phosphorylation of nucleosides is the target goal, as there is currently no chemical
synthesis of nucleoside phosphates, especially triphosphates, which works with high
selectivity for all nucleoside substrates.
Other nucleoside phosphate derivatives such
as nucleoside tetraphosphates also find important applications in DNA sequencing and
labeling. 43 Typically, nucleotide chemical synthesis suffers from low yield; since the
reactions of 7 with methanol and with cholesterol are quantitative, 7 might serve as
a potent nucleoside phosphorylating agent.
Preliminary results from treatment of [PPN] 2 [P 4 01 11 with adenosine suggested
that phosphorylation of adenosine occured quantitatively at both 3'- and 5'-positions
to afford a mixture of adenosine metaphosphate products. Selectivity of phosphorylation is a typical problem encountered in nucleotide synthesis due to similar reactivities
of 3'- and 5'-positioned hydroxyl groups of the nucleosides. Increasing the specificity
of nucleoside phosphorylation reaction is future work to be explored. Addition of auxiliary reagent has been shown to affect the selectivity of phosphorylation reaction, and
could potentially pave the way to cleanly access nucleoside tetramnetaphosphates. 44
2.2.3
Synthesis of IPPN]3P 6 Ol7 H] (8)
A new metaphosphate anhydride was discovered upon treatment of [PPN
3 [P 6 0 1iH
3]
with DCC (Schemie 2.5). The formation of insoluble white product was associated
with the reaction, indicating the DCU byproduct of the dehydration reaction. The
reaction was quantitative, and the product which was proposed to be [PPNI 3[P6 0 17 H]
was isolated in 88% yield. The
31
P{ 1 H} NMR spectrum of 8 features four distinct
broad peaks at 6 -25.90 (br, 2 P), -27.05 (br, 1 P), -27.69 (br, 1 P), and -37.98 (br,
2 P) ppm. The broad peaks in
31
P{ 1 H} NMR spectrum are explained by dynamic
proton exchange among the four distinct phosphate units. The signal at 6 -37.98
ppm is indicative of branched phosphate, thus supporting the assignment of this
metaphosphate anhydride.
1
H NMR (CD 3 CN) spectrum of 8 features a very broad
signal at 6 12.47 ppm (br, 1 H, P--OH).
In an unpurified MeCN solution not dried over 4
NMR signals at 6 -27.05
and -27.69
A molecular sieves, the
31
p{ 1 H}
ppm were split into triplets. Such similar be-
46
havior was observed for 9 when inultiplets in
31
p{ 1 H} NMR spectrum were resolved
by addition of water to the sample. The phenomenon was believed to be related to
hydrogen bonding in the protonated tetrametaphosphate ring and the fluxionality
of the ring, which was altered upon the introduction of water. Although not rigorously proven, the behavior gave useful information regarding the connectivity of the
phosphates in 8 and led to the proposed structure as depicted in Scheme 2.5.
0,
0o
\/
S
:1
O==P
H "'
--
H""'""OOZZZ-
0
00
0 P=OP
\
(PPN)3
0
(PPN.) 3
DCC
MeCN
DCU
0
\
O
PY H~I
,...-PW
O
-0
-~~
O
O: 0
Ik
00.
0
Scheme 2.5: Synthesis of IPPN]3[P6 O 17 H] from the dehydration of [PPN]3[P 6 O 1sH 3]
by DCC
2.3
Conclusions
Tetrametaphosphate anhydride [PPN] 2 [P 4 011 1 (7) was synthesized from the dehydration of fPPN1 2 [P 4 0 12 H 2 ] and facilely isolated in high purity. The availability of clean
7 enabled the studies of its reactivity, particularly its reaction with nucleophiles.
Alcoholysis of [PPN12[P 4 011
proceeded quantitatively and selectively to yield or-
ganic tetrametaphosphate esters. Dehydration of [PPN]31P 60 1 H 3] resulted in a new
metaphosphate anhydride IPPN]3[P6 O1 7H] (8).
7 and 8 are promising candidates
for nucleoside phosphorylating agents, as nucleophilic cleavage at phosphoanhydride
bond proceeds quantitatively and facilely, presenting a way to access new nucleotide
derivatives.
47
2.4
Experimental Details and Procedures
General Methods
All operations were performed in a Vacuum Atmospheres drybox under an atmnosphere of purified nitrogen. [PPN] 2 [P 4 0
12 H 2 ]
and [PPNI 3 [P6 0,SH 3 ] were prepared as
described in Section 1.5. DCC and cholesterol were purchased from Sigma Aldrich
and used as received.
Dry MeCN, DCM, and THF were dried and deoxygenated
by the rethod of Grubbs using a system built by SG Water USA, LLC and stored
over 4
A
molecular sieves. 4
A
molecular sieves were dried under reduced pressure
at a temperature above 200 'C over the course of one week. Deuterated acetonitrile
and deuterated chloroform were obtained from Cambridge Isotope Laboratories and
dried over 4
A molecular sieves
prior to use.
1H, 31 P,
and
31
p{'H} NMR spectra were
recorded on Varian Mercury-300 or Bruker AVANCE-400 spectrometers.
1H NMR
chemical shifts are reported with respect to internal solvent residual (CD 3 CN, 6: 1.94
ppm; CDCl 3 , 6: 7.26 ppm).
31P
NMR chemical shifts are reported with respect to an
external reference (85% H 3PO 4 , 6: 0.00 ppm).
13C
NMR chemical shifts are reported
with respect to internal solvent residual (CH 3 CN, 6: 118.26 ppm; CDCl 3 : 77.16 ppm).
Infrared spectra were recorded on a Bruker TENSOR37 FT-IR Spectrophotometer.
Elemental analyses were performed by Robertson Microlit Laboratories, Inc.
Synthesis of [PPN 2 [P 4OuJ (7)
[PPN2[P 4 01 2 H 2 ] (2.0046 g, 1.437 mmol, 1.0 equiv) was suspended in MeCN (40 mL).
To the stirring suspension of [PPN
2
1P 4 01 2 H 2 ] was
added DCC (0.300 g, 1.453 lnmmol,
1.01 equiv) as a solid. Upon addition, the reaction mixture became less cloudy, then
white solid started to precipitate. The reaction mnixture was allowed to stir at room
temperature for 2 h. The mixture was then filtered through a pad of celite. Volatiles
from the filtrate were removed under reduced pressure to give a white solid. The
product was suspended in THF (10 mL), and isolated by filtration to afford 7 as
white powder (1.8251 g, 1.325 mmimol, 92% yield).
48
Eleir. Anal. Found: C, 62.56; H, 4.56; N, 2.03%. Calc. for C 7 2 H 6oN 2 OuPs: C,
62.80; H, 4.39; N, 2.03%. 1H NMR (CD 3 CN, 300 MHz, ppm) 6 7.4-7.8 (in, 60 H, HAr).
31
P{1H} NMR (CD 3 CN, 162 MHz, ppm) 6 21.96 (s, 4 P, [PPNI+), -24.40 (t, 2 Jpp
29 Hz, 2 P), -32.51
(t, 2 Jpp = 29 Hz, 2 P).
13
C NMR (CD 3 CN, 100 MHz, ppm) 6
133.61 (s), 132.26 (in), 129.38 (in), 127.25 (d, 1 Jpc =107 Hz). ESI-MS (-)(CH 3 CN,
in/z): 300.8838 (100%, [P 4 0112-+H+). IR (ATR, cr~-1): v 1262 (s), 995 (s).
Synthesis of cholesteryl hydrogentetrametaphosphate [PPNL-
[P40 10 (OH)(R)J (10)
A solid mixture of [PPN]2[P4l0lI (0.1949 g, 0.142 mmnol, 1 equiv) and cholesterol
(0.0549 g, 0.142 mmol, 1.0 equiv) was dissolved in DCM (2 miL). The reaction mixture
was stirred for 6 days. Volatile materials were then removed under reduced pressure
to afford 10 as white solid (0.2155 g, 0.122 mnmnol, 86% yield).
1H NMR (CDCl 3 , 400 MHz, ppm) 6 11.15 (br, 1 H, P-OH), 7.4-7.8 (in, 60 H,
HAr),
5.24 (m, 1 H, C=CH), 4.44 (in, 1 H, 0-CH), 0.5-2.6 (m, 44 H, R).
31
P{'H}
NMR (CH 2 Cl 2 , 121.5 MHz, ppm) 6 21.66 (s, 4 P, [PPNI+), -23.29 (t, 2 JeP = 25 Hz,
1 P), -25.24 (dd,
2
Jpp
= 25, 28 Hz, 2 P), -27.56 (t, 2 JpP = 28 Hz, 1 P).
(CH 2 Cl 2 , 121.5 MHz, ppm) 6 21.66 (s, 4 P, [PPNJ+), -23.29 (t, 2 JpP
-25.24
13
(dd, 2 JpP = 25, 28 Hz, 2 P), -27.56 (td,
2
Jpp
= 25 Hz,
3
JHP
31
P NMR
25 Hz, 1 P),
7 Hz, 1 P).
C NMR (CDCl 3 , 100 MHz, ppin) 6 139.97 (s, C=CH), 133.78 (s, IPPN1+), 131.77
(im,
[PPNJ+), 129.40 (in, [PPNI+), 126.58 (d,
1
Jpc =107 Hz, [PPNJ+), 121.67 (s,
C=CH), 70.87 (s, PO-0, 11-56 (im, R). ESI-MS (-)(CH 2Cl 2 , m/z): 343.06 (100%,
[P 4 01o(OH)(R)]2-). IR (ATR, cnrm): v 1262 (s), 1113 (s), 976 (s).
Synthesis of [PPN] 3 [P6 O 7 H] (8)
[PPN] 3 [P 6 01sH 3] (0.2038 g, 0.0934 nmnol, 1 equiv) was dissolved in MeCN (2 nL).
To the stirring solution of 5 was added DCC (0.0954 g, 0.462 mnmol, 4.95 equiv)
as solid. Formation of white precipitate was observed almost irimediately after the
addition. The reaction mixture was stirred for 5 mini, then was filtered through a glass
49
rmicrofiber filter. Volatiles were removed from the filtrate under reduced pressure to
yield a white solid. The solid was suspended in THF (3 irL) for 1 h. Supernatant
was decanted, and the solid was further washed with THF (3 mL), and dried in vacuo
to afford [PPN]3[P 6 O1 7 H]-2THF as white solid (0.1821 g, 0.082 mmnrol, 88% yield).
Elemn. Anal. Found: C, 60.55; H, 4.83; N, 1.90%. Calc. for C 116 H 107 N 3 0 1 9P 12 : C,
62.79; H, 4.86; N, 1.89%.
1H
NMR (CD 3 CN, 400 MHz, ppm) 6 12.47 (br, 1 H, P-OH),
7.4-7.8 (in, 90 H, HAr), 3.63 (in, 8 H, OCH 2 ), 1.79 (in, 8 H, OCH2 CH2 ).
31
P{ 1 H}
NMR (CD 3 CN, 121.5 MHz, ppm) 6 22.24 (s, 6 P, [PPN]+), -25.62 (br, 2 P), -26.81
(br, 1 P), -27.54 (br, 1 P), -37.73
(br, 2 P).
134.57 (s), 133.19 (in), 130.34 (m), 128.16 (d,
13
C NMR (CD 3 CN, 100 MHz, ppmi) 6
1 Jpc
=108 Hz), 68.23 (s, THF), 26.19
(s, THF). IR (ATR, cm--1): v 1261 (s), 1112 (s), 995 (s).
X-ray Data Collection and Structure Determinations
Single crystal X-ray diffraction data were collected at 100 K on a Siemens Platform
three-circle diffractomneter coupled to a Bruker-AXS Smart Apex CCD detector, using
graphite-monochromated Mo-Ka radiation (A= 0.71073
A).
Colorless crystals of [PPN] 2 [P 4 01 1J (7) were grown from vapor diffusion of Et 2 0
into a concentrated solution of 7 in MeCN. 7 crystallizes in the mnionoclinic space
group P2 1 /c with one anion of [P 4 011
2
-,
one entire cation of [PPNJ+, and two half
[PPN]+ countercations in the asymmetric unit. The model contains no disorder, and
no restraints were applied.
50
[PPN]2[P40uI (7)
X8_13013 / 998202
C 72 H 6oN 2 OnIPs, 1376.98
0.26 x 0.22 x 0.14
100(2)
0.71073
)
Reciprocal Net code / CCDC No.
Empirical formula, FW (g/mrol)
Crystal size (mm 3
Temperature (K)
Wavelength (A)
Crystal system, Space group
Monoclinic, P21 /c
a (A), a(o)
b
(A),
17.4891(13), 90.00
15.2366(11), 104.2850(10)
25.1850(18), 90.00
6503.6(8)
4
1.406
0.279
2856
j(O)
)
Volume (A 3
Z
)
)
Density (calc., g/cm 3
Absorption coefficient (mnmn m
F(000)
Theta range for data collection (0)
Index ranges
Reflections collected
Independent reflections, Rit
Completeness to 0 = 25.242'
Refinement method
Data / restraints / parameters
Goodness-of-fit on P2
-24<h<24
-21<k<21
-35<1<35
183927
19837 (0.0566)
100%
Full-imatrix least-squares on P2
Final R indices [I > 2o-(])
R indices (all data)
3
19837 / 0 / 841
1.044
RI = 0.0407, wR 2 = 0.1010
R1 = 0.0581, wR 2 = 0.1127
n/a
0.634 and -0.565
)
Extinction coefficient
Largest diff. peak and hole (e-A-
1.201 to 30.507
Table 2.1: Crystallographic data for [PPN]2[P 4
51
OuI
52
Appendix A
Determination of Acid Dissociation
Constant of [PPN] 2 [P 4 0 12 H 2 ] in
Acetonitrile Solution
The acid dissociation of [P 4 0 1 2H 212- is one of the four steps in the ionization of
tetrametaphosphoric acid H 4 P 4 0 12 (Eqn. A.1). Herein, pKa3 value which corresponds
to the acidity of [PPN]2[P 4 0 12 H 2 ] (Eqn. A.1c) was determined.
H4 P 40
12
[P 4 0 12 H 3]
[P4012H2]2[P 4 0 12 H] 3 ~
]~ + H+
-
[P 4 0
12 H 3
-
[P 4 0
12
+
H 2 ] 2 - + H+
(A.1a)
(A.Ib)
[P40 12H] 3 - + H+
(A.1c)
[P4012]4
(A.Id)
+ H+
It is rather simplistic to assume that tetrametaphosphate acids exist in monomeric
forms in MeCN solution, as it is strictly not true as observed in 3. However, it is
more reasonable to assume that tetrametaphosphate acids bearing fewer than two
protons are monomeric because the tetrametaphosphate ring can stabilize those protons via strong intramolecular hydrogen bonds (Section 1.3.7).
Spectrophotometric
titration was employed to determine the pKa of IPPN12IP 4 01 2 H 2 ] in MeCN, following
53
M
.
.
-
.- - - __
an established procedure. 45 Triethylamine (NEt3 ) solution was used as a basic titrant.
Determination of pKa in weakly solvating solvents such as MeCN is complicated by
the poorly-defined acidity of the medium and the formation of homoconjugate complex between the acid and its conjugate base; thus, 2,4-dinitrophenol (2,4-DNP) was
used as a reference (pKa=1 6 .66 in MeCN). 46 The pKa of 2 was determined from the
extent of the chemical equilibrium between 2 and 2,4-DNP reference (Eqn. A.2).
[P 4 0 12H 2] 2 - + [C 6 H 3 N 2 05 ]- # [P 40 12 H] 3 - + C6 H 4N 2 05
(A.2)
UV-vis absorption spectra of the analyte were recorded over the course of the
titration with NEt3 (Fig. A-1). No significant shift of the absorption spectra was
observed as indicated by the sharp isosbestic point, thus homoconjugation and heteroconjugation were assumed negligible within the system. 46,47
0.50.4-
0.11
0350
300
400
X (nm)
450
500
550
.
Figure A-1: UV-vis absorption spectra of titration of 2 and 2,4-DNP with NEt3
The absorbances at 372 and 426 nm corresponded to 2,4-dinitrophenolate, and were
monitored over the course of the titration.
The concentrations of [P 4 0 12 H 2 12- ([HAi]), 2,4-DNP ([HA 2I), [P 4 0 12 H]- ([A-i),
and 2,4-dinitrophenolate
DNP
(ADNP),
([A-I)
were calculated using the initial absorbance of 2,4-
the absorbances over the course of the titration (AA), and the ab-
sorbance at which 2,4-DNP existed only in acid form after addition of TfOH to the
54
analyte (AO).
titrant
(CNEt 3 )
The total molar concentrations of 2 (CI), 2,4-DNP (C2), and NEt3
were obtained from moles of corresponding reagents added to the
[HA 2] =2
-
CNEt3
- (AA
(A)3
-
NP
[A] =CNEt 3
A)E~j(A.3
[A]
=
(AA - A
(A-NP
-
+
-
(A
-
C1
[HA 1 ]
-
analyte, and were used in the calculation (Eqn. A.3).
)/Elj
The molar absorptivity of 2,4-dinitrophenolate (EA) was obtained by a separate titration of 2,4-DNP with NEt 3 titrant. Two maximum absorption peaks at 372 and 426
nm1 were chosen for the calculation, where the absorption of 2,4-DNP was practically
negligible. There was no absorption from 2 in the region 350 to 500 nm of interest in
the UV-vis spectrun.
The relative acidity could be calculated from Eqn. A.4:
HA 1 +A-
'Ai-+HA
2
[A-] [H A2
ApKa = pKa(HA2 ) - pKa(HAI) = log [A1] [HA
2]
[Ay] [HA 1 ]
(A.4)
The acidity determination using 12 data points from two absorption peaks over
the course of the titration resulted in a pKa3 value of 15.83, with a standard deviation
of 0.11. The relative acidity was referenced to that of 2,4-DNP of which the pKa is
16.66 in MeCN. 4 6
55
56
Appendix B
Optimized Geometry of
[P 6 018H2(H30)212Geometry Optimization calculation was performed using ORCA 2.9 quantum chemistry program package.
48
The VWN5 functional was implemented for the calculation,
with 6-311G++(2d,2p) basis set.4951 Initial coordinates were taken from the crystal
structure of 6. Only the monomeric structure was used as a model for the calculation,
ignoring the LBHBs between hexametaphosphate rings found in the crystal structure.
The optimized structure as shown in Fig. B-1 features the acidic proton between
the phosphate and the water molecule residing more favorably on the water molecule.
The calculated
...
0 distance is 2.49
A,
supporting the LBHB assignment in the
crystal structure. Another geometry optimization was performed using initial coordinates of which the acidic hydrogen atoms are placed on the hexametaphosphate to
ensure there does not exist another local minimum in energy landscape.
The same
resulting structure was obtained.
The fact that the calculation does not take into account intermolecular hydrogen bonds which link the hexametaphosphate rings into a one-dimensional polymer
was mediated by the argument of cooperativity of hydrogen bonds in the metaphosphate.
14
If two of the unprotonated phosphates were to accept hydrogen bonds, anti-
cooperative effect would favor the hydronium adduct configuration more. If the two
dangling hydrogen atoms were to donate hydrogen bonds, cooperative effect would
57
Figure B-1: Calculated structure of P 6 0 18 H 2 (H 3 0)2 ]2- at 6-311G- -(2d,2p)
level
disfavor the hydronium adduct configuration with, presumably, similar magnitude.
Therefore, the monomeric structure used in this calculation is expected to have similar bonding properties to the hydronium ions as the polymeric structure found in the
crystal structure.
58
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