NMR and symmetry in bisphosphonates R1R2N-CH[P(O)(OMe)2]2

Article abstract of DOI:10.1080/10426507.2017.1295966

(Amino-methylene)bisphosphonates R¹R²N-CH[P(O)(OMe)₂]₂ bearing achiral and chiral substituents (R¹ = Ph, R² = H, Me; and R¹ = PhCH(Me), R² = Me, Bn) were synthesized a

Full text of DOI:10.1080/10426507.2017.1295966

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
NMR and Symmetry in Bisphosphonates R1R2N-
CH[P(O)(OMe)2]2 In memoriam of Professor Harry
R. Hudson
Nader Amadeu, Erika Bálint, Winfried Boenigk, Ádám Tajti, Gerhard Hägele,
Christoph Janiak & György Keglevich
To cite this article: Nader Amadeu, Erika Bálint, Winfried Boenigk, Ádám Tajti, Gerhard Hägele,
Christoph Janiak & György Keglevich (2017): NMR and Symmetry in Bisphosphonates R1R2N-
CH[P(O)(OMe)2]2 In memoriam of Professor Harry R. Hudson, Phosphorus, Sulfur, and Silicon and
the Related Elements
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1295966
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NMR and Bisphosphonates
NMR and Symmetry in Bisphosphonates R1R2N-CH[P(O)(OMe)2]2
In memoriam of Professor Harry R. Hudson
Nader Amadeu1a, Erika Bálint2, Winfried Boenigk1b, 3, Ádám Tajti4a, Gerhard Hägele1c*,
Christoph Janiak1d, György Keglevich4b
1Institute of Inorganic Chemistry and Structural Chemistry, Heinrich-Heine-University
Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany; a) nader@uni-
duesseldorf.de; c) haegele@uni-duesseldorf.de; d) janiak@uni-duesseldorf.de
2MTA-BME Research Group for Organic Chemical Technology, 1521 Budapest,
Hungary; ebalint@mail.bme.hu
3RÜTGERS Germany GmbH, Kekuléstraße 30, D-44579 Castrop-Rauxel, Germany;
winfried.boenigk@raincarbon.com
4Department of Organic Chemistry and Technology, Budapest University of Technology
and Economics, 1521 Budapest, Hungary; a) tajti.adam@mail.bme.hu; b)
gkeglevich@mail.bme.hu
Abstract
(Amino-methylene)bisphosphonates R1R2N-CH[P(O)(OMe)2]2 bearing achiral and
chiral substituents (R1 = Ph, R2 = H, Me; and R1 = PhCH(Me), R2 = Me, Bn) were
synthesized and characterized in CDCl3 by 1H, 1H{31P}, 13C{1H}, 31P{1H}, and 31P NMR
spectra. [P(O)(OMe)2]2 fragments from achiral compounds give rise to complex 1H NMR
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1
spectra characteristic for the [A3M3X]2 H NMR spectra while chiral compounds yield
A3G3M3T3XY type spectra. Aspects of molecular symmetry governing the multiplet
patterns are discussed and precise spectral parameters are calculated by line-shape
iterations.
Keywords
(Amino-methylene)bisphosphonates, methyl esters, multinuclear NMR, spin
systems, line-shape iterations, grid net search.
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Introduction
H. Gross and B. Costisella reported the first synthetic routes to tetraethyl
(dimethylamino-methylene)bisphosphonate Me2N-CH[P(O)(OEt)2]2 1.1-3 Quaternization
-,
-
of 1 at nitrogen led to Me3N+-CH[P(O)(OEt)2]2 X- (X- = CH3OSO3 J-, ClO4 ) 2, which was
converted into a betaine Me3N+-C-[P(O)(OEt)2]2 3 and a carbanion sodium salt
Me2N-C-[P(O)(OEt)2]2 Na+ 4.4,5 Although these tetraethyl esters 1-4 possess a mirror
plane in the molecular structure, their methylene protons are pairwise chemically non-
equivalent (diastereotopic), giving rise to separate resonance lines. Hence, the very
complex 1H NMR spectra of 1-4 representing [(ABM3)(CDN3)X]2 spin systems for the
corresponding [P(O)(OCH2CH3)2]2 fragments were not fully explained in the early
studies using low field NMR spectrometers. Only partial results were accessible and
reported.
A tetramethyl ester Me2N-CH[P(O)(OMe)2]2 5, which is analogous to 1, is conveniently
accessible according to the following scheme:2
+ 2 HP(O)(OMe)2
Me2NCH(OMe)2
Me2NCH[P(O)(OMe)2]2
5
-2 MeOH
While Me2N-CH[P(O)(OEt)2]2 1 is stable at ambient temperature the liquid
Me2N-CH[P(O)(OMe)2]2 5 rearranges at room temperature in a slow auto-quaternization
to asymmetric Me3N+-CH[P(O)(OMe)2][P(O)(OMe)O-] 6, a solid, crystalline, betainic
form.
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5
Me3N+CH[P(O)(OMe)2][P(O)(OMe)O-]
6
In subsequent years (amino-methylene)bisphosphonic acids and esters have attracted
much practical interests in synthetic chemistry. With the advent of Green Chemistry6
attention was drawn towards microwave (MW)-assisted syntheses of
(amino-methylene)bisphosphonates by three-component condensations pioneered by
the Budapest team of G. Keglevich and described in Ref. 7.7 A collection of
corresponding references for this interesting field is listed in E. Bálint´s recent paper.7
For NMR spectroscopic reasons we wanted to disturb the molecular symmetry of
(amino-methylene)bisphosphonates R1R2N-CH[P(O)(OMe)2]2 by introducing asymmetry
at nitrogen by using R1 ≠ R2 or at a carbon in substituent R1. Applying MW techniques
described in7 the following compounds were obtained:
MW, N2
110°C, 1h
R1R2NH + (MeO)3CH + H(P)(OMe)2
3.5-4.5 eq.
R1R2N-CH[P(O)(OMe)2]2
7 - 10
- 3 MeOH
no solvent
Nitrogen in compounds Ph-N(H)-CH[P(O)(OMe)2]2 7 and
Ph-N(Me)-CH[P(O)(OMe)2]2 8 undergo rapid inversion on the NMR time scale at room
temperature and, hence are effectively non-chiral under NMR aspects, a dynamically
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averaged spectrum of the invertomers is observed. But the α-carbon from the
α-methylbenzyl substituent Ph-CH(CH3) in Ph-CH(Me)-N(Me)-CH[P(O)(OMe)2]2 9 and
Ph-CH(Me)-N(CH2Ph)-CH[P(O)(OMe)2]2 10 is chiral and, hence compounds 9 and 10
give rise to interesting hitherto unknown NMR spectra of asymmetric bisphosphonates,
which will be described and analyzed in the following sections.
Results and discussions
Symmetric methyl esters R1R2N-CH[P(O)(OMe)2]2 (R1 = R2 = achiral) give rise to
trivial spectra for corresponding R1R2N-CHP2 parts but rather complex patterns for
[P(O)(OMe)2]2 fragments.
Example 1: Me2N-CH[P(O)(OCH3)2]2 5
The 1H NMR spectrum of (CH3)2N-CH[P(O)(OCH3)2]2 5 is characterized by
simple triplets for (CH3)2NHP2 (due to 4JPH coupling) and NCHP2 (2JPH), while a complex
[A3M3X]2 pattern is obtained for the [P(O)(OCH3)2]2 unit. The geminal methoxy groups
from P(O)(OCH3)2 in the neighborhood of a prochiral carbon center are chemically non-
equivalent (diastereotopic). However, they are pairwise chemically equivalent to the
methyl protons denoted by A’ and M’ in the other P(O)(OCH3)2 group as depicted in This
[A3M3X]2 spin system is characterized by four parameters, which are linear
combinations of the PH-coupling constants 3JPH and 5JPH, in addition to the geminal PP-
coupling constant 2JPP:
5
1
2
3
NAX = JAX + JAX´ = 3JPH + JPH
LAX = JAX - JAX´ = 3JPH - JPH
5
NMX = JMX + JMX´ = 3JPH + JPH
5
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5
4
LMX = JMX - JMX´ = 3JPH - JPH
2
5
JXX´ = JPP
n
All other long range couplings of type JHH are zero. This complex spectrum was not
fully understood during those pioneering years of bisphosphonate chemistry. Using the
guidelines developed for the [AaMmX]2 type spectrum of [Me(tBu)P(S)]2 and related
structures8 attempts were made to analyze the 1H NMR spectrum of this [P(O)(OCH3)2]2
fragment shown in Figure 2 by grid net search simulations. The resulting spectral
parameters are listed in Table 1 below.
So a first guess of the characteristic geminal coupling constant 2JPP yielded a numerical
value near 16 Hz for the symmetric compound 5. The spectral habitus of [AaMmX]2
spectra is invariant to the sign of 2JPP, hence only the absolute values for 2JPP are
obtained. 2JPP is not accessible by 13C satellites in the 31P{1H} NMR spectrum of
symmetric 5, only a simple singlet was observed since 2JPH and 4JPH are too small, as
discussed in subsequent sections. This low value of 2JPP seemed agreeable and
supported by further observations:
1) The asymmetric betaine Me3N+-CH[P(O)(OMe)2][P(O)(OMe)O-] 6 gives rise to an XY
type 31P{1H} NMR spectrum but exhibits two singlets only where 2JPP is not resolved,
and hence close to or equal zero Hz. Data for 6 are listed in Table 2.
2) For two chiral (1-hydroxy-methylene)bisphosphonic acids R*-C(OH)[P(O)(OH)2]2
numerical values of 21.1 Hz and 27.5 Hz were found for 2JPP. This interesting
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observation was reported by C. E. McKenna et al. in a publication dealing with aspects
of medicinal chemistry.9
Examples 2: Achiral Bisphosphonates: Ph-N(H)-CH[P(O)(OMe)2]2 7 and
Ph-N(Me)-CH[P(O)(OMe)2]2 8
Tetramethyl (phenylamino-methylene)bisphosphonate 7 is identified in 1H NMR
by a triplet for NCHP2 centered at 4.2413 ppm and a corresponding coupling constant
2JPH of -23.9 Hz. The [P(O)(OCH3)2]2 fragment shows two overlapping deceptively
simple triplets (dst) for the A3 and M3 parts of an [A3M3X]2 system. Nonequivalent methyl
groups POCH3 (I) and POCH3 (II) are located at 3.7965 and 3.8149 ppm with NAX
10.8 Hz and NMX = 10.8 Hz. (See Figure 3).
=
Manual grid net search for simulations with DAISY10 under TOPSPIN10 led to the
missing parameter 2JPP = 60 ± 5 Hz, which is surprisingly high. Further coupling
constants are found in ranges: 3JPH = 10.3 to 10.8 Hz and 5JPH = 0.5 to 0 Hz. Hence the
linear combined parameters LAX and LMX are obtained with 3JPH - 5JPH = 9.8 to 10.8 Hz
(special case with NAX = NMX and LAX = LMX). Expectation ranges given above are valid
for an experimental spectral half width HW = 2 Hz.
In the 500 MHz 1H NMR spectrum the phenyl group C6H5-N in 7 appears with
broadened lines exhibiting at first sight three patterns: doublet (6.7016, Hortho), triplet
(7.2037, Hmeta), and triplet (6.7994, Hpara). Corresponding coupling constants nJHH (n =
3-5) for this [AC]2B spectrum are accessible by iteration only.
Results reported above are obtained from solutions of 7 in CDCl3, aged about
one week and measured at 500 MHz 1H NMR at Düsseldorf. The NH proton is revealed
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as a very broad line around 3.5 ppm close to the methoxy region. But if 7 is freshly
prepared, dissolved in dry CDCl3, and rapidly measured, than a spectrum is obtained,
where the NH proton is coupled with the CH proton in the HNCHP2 fragment
approximating the B-part of an ABMX2 system. Lines are selectively broadened by the
quadrupolar nitrogen 14N (M-part) as shown in Figure 4:
13C{1H} NMR spectra confirm as well also reflect the molecular symmetry of 7:
NCHP2 is characterized by a triplet at 50.10 ppm with 1JPC = 147.8 Hz. Two non-
equivalent methoxy groups POCH3 (I) and POCH3 (II) are responsible for two
deceptively simple triplets at 53.85 and 54.29 ppm with NC (I) = 5.8 and NC (II) = 5.6 Hz
resp. In this context two linear combinations NC and LC are defined:
6
7
NC = 2JPH + 4JPH
LC = 2JPH - 4JPH
If 4JPH is negligibly small, than NC represents effectively the geminal coupling 2JPC.
A
corresponding spectrum for the methoxy region of 7 is shown in the top trace of Figure
5:
The phenyl group C6H5-N in 7 appears in text book quality with three
characteristic singlet signals: (113.80 ppm, Cortho), (129.34 ppm, Cmeta), (119.43 ppm,
Cpara). In addition a triplet is observed (145.91 ppm, Cipso) with 3JPC = 4.0 Hz.
Finally the 31P{1H} NMR spectrum of 7 exhibits a singlet at δP = 21.11 ppm. Since
І2JPPІ >> ІLCІ the relevant coupling parameter 2JPP is not accessible neither by 13C{1H}
nor by 31P{1H} NMR techniques for AXX´ or AXY type systems of the COPCP fragment.
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The evaluation of NMR spectra from tetramethyl
(N-methylphenylamino-methylene)bisphosphonate 8 follows routes described above. An
additional signal in 1H NMR is observed for the N-CH3 group: a broadened triplet at δH =
3.1610 ppm with 4JPH = 0.9 Hz. By 13C{1H} NMR the N-methyl group N-CH3 is detected
at δC = 35.95 ppm as a singlet, where 3JPC is not resolved. The 31P{1H} NMR spectrum
of 8 exhibits a singlet at δP = 21.34 ppm.
Data for compounds 7 and 8 are listed in Table 3 and Table 4.
Examples 3: Chiral bisphosphonates: Ph-CH(CH3)-N(CH3)-CH[P(O)(OCH3)2]2 9 and
Ph-CH(CH3)-N(CH2Ph)-CH[P(O)(OCH3)2]2 10
Introducing the chiral substituent R1* = Ph-CH(CH3) into the skeleton of
tetramethyl (amino-methylene)bisphosphonates R1*R2-NCH[P(O)(OCH3)2]2 removes the
symmetry and chemical equivalence for the pairs of phosphorus atoms and POCH3
groups, which were found in achiral bisphosphonates 7 and 8. Hence the significant
NCHP2 group gives rise to XY type (as opposed to X2) spectra in 31P{1H} NMR, as
shown in Figure 6 below. XY-type spectral analysis yielded the following numerical data
for 9: δP(PX) = 24.04 ppm, δP(PY) = 22.96 ppm, 2JPP = 61.2 Hz. 10:
δP(PX) = 24.66
ppm, δP(PY) = 23.87 ppm (br), 2JPP = 64.9 Hz. By XY analysis only absolute values for
2JPP are accessible. It seems noteworthy that PY of 10 reveals a broader spectral half
width than PX. This might indicate a dynamic situation, possibly slow intramolecular
rotations in 10.
In addition the proton NCHP2 of 9 appears in 1H NMR as a doublet of doublets
(instead of a triplet) with parameter: δH = 3.6888 ppm, 2JPH = -26.5 Hz; 2JPH = -24.3 Hz.
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In 1H NMR of 10 the NCHP2 proton is obscured by methoxy resonances, but 1H{31P}
reveals δH = 3.6928 ppm. Hence 2JPH data are not accessible for 10.
The [P(O)(OCH3)2]2 fragments are easily understood: A3G3M3T3XY spin systems
are expected in 1H NMR spectra following Figure 7:
Indeed four doublets for the individual methoxy groups POCH3 (I) to (IV) are observed
by 1H NMR. Vicinal couplings 3JPH are obtained, while the long range 5JPH is not
resolved. By decoupling the phosphorus spins XY four singlets are seen in 1H{31P}
NMR. (See Figure 8 below. Numerical data from spin analysis are listed in Table 5.
The evaluation of 13C{1H} NMR spectra of 9 and 10 follows outlines given above.
Numerical results are summarized in Table 6. Here it seems sufficient to point interests
towards unusual observations: Signals for 13C spins marked bold C6H5-CH(CH3)-N(CH2-
C6H5)-CH[P(O)(OCH3)2]2 are broadened. And the 31P{1H} signal of PY in 10 is
broadened as well (see Figure 6). Those effects indicate slow intramolecular rotations
in the sterically crowded structure of 10.
Conclusions
Novel (amino-methylene)bisphosphonates are accessible via microwave-assisted
synthesis. R1R2N-CH[P(O)(OMe)2]2 with achiral substituents R1 and R2 give rise to
complex [A3M3X]2 spectra for the [P(O)(OMe)2]2 fragments. Laborious grid net search
led to tentative data around 60 Hz for geminal coupling constants 2JPP. Those results
are confirmed by accurate data for 2JPP obtained from chiral R1*R2N-CH[P(O)(OMe)2]2
where R1* = Ph-CH(Me). Corresponding A3G3M3T3XY spectra are presented. All
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functional groups in achiral and chiral bisphosphonates 7-10 were characterized by
NMR data.
Experimental
NMR spectra were measured using spectrometers at Düsseldorf (90, 500, 600
MHz proton frequency, BRUKER, Karlsruhe, Germany), and Norwich (100 MHz for 1H,
VARIAN). Solvent: CDCl3. References: internal TMS for 1H and 13C, external 85%
H3PO4 for 31P NMR. Spectra were evaluated with TOPSPIN10 while simulations and
iterations were performed with DAISY.10 Compounds (CH3)2N-CH[P(O)(OCH3)2]2 5 and
(CH3)3N+-CH[P(O)(OCH3)2][P(O)(OCH3)O-] 6 were provided by Henkel KGaA,
Düsseldorf, Germany. Compounds 7-10 were synthesized by the Budapest team:
General procedure7 for tetramethyl (amino-methylene)bisphosphonates (7-10)
A mixture of 1.0 mmol amine (aniline: 0.09 mL, N-methylaniline: 0.11 mL, (R)-N-
methyl-α-methylbenzylamine: 0.15 mL, (R)-N-benzyl-α-methylbenzylamine: 0.21 mL),
1.0 mmol (0.11 mL) trimethyl orthoformate and dimethyl phosphite [3.5 mmol (0.32 mL)
or 4.5 mmol (0.41 mL)] was heated at 110 °C for 1 h in a closed vial under N2
atmosphere in a CEM Discover Microwave reactor equipped with a pressure controller
applying 10-15 W. The crude products 7-10 were purified by column chromatography on
silica with dichloromethane / methanol (97:3) or ethyl acetate as eluents. Following this
general procedure compounds 7-10 were prepared:
Tetramethyl (phenylamino-methylene)bisphosphonate 7
Yield: 63% (0.10 g) of compound 7 as pale yellow crystals; Mp: 168-169. This
compound was reported in our recently published paper.7 C11H19NO6P2. [M]+ = 323.1.
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GC-MS: [M]+ = 323. LC-MS: [M+H]+ = 324.1. HRMS: [M+H]+ = 324.0760. For NMR data
see text above.
Tetramethyl (N-methylphenylamino-methylene)bisphosphonate 8
Yield: 24% (0.08 g) of compound 8 as colorless oil. C12H21NO6P2. [M]+ = 337.1. GC-MS:
[M]+ = 337. For NMR data see above.
Tetramethyl (N-methyl-α-methylbenzylamino-methylene)bisphosphonate 9
Yield: 38% (0.14 g) of compound 9 as colorless oil. C14H25NO6P2. [M]+ = 365.1. LC-MS:
[M+H]+ = 366.1. For NMR data see text above.
Tetramethyl (N-methyl-α-methylbenzylamino-methylene)bisphosphonate 10
Yield: 36% (0.16 g) of compound 10 as colorless oil. C20H29NO6P2. [M]+ = 441.2. LC-
MS: [M+H]+ = 442.2. For NMR data see text above.
Acknowledgements
Thanks are due to Ms. Beate Rau for dedicated NMR measurements using the
500 MHz and 600 MHz spectrometers at Düsseldorf. Compounds 5 and 6 were
provided by Dr. W. Plöger, formerly Henkel KGaA, Düsseldorf, Germany. Special
thanks are due to Prof. R. K. Harris, formerly UEA Norwich, GB, for supporting our early
attempts to understand the [A3M3X]2 spectra. Particular thanks are due to the Hungarian
Scientific Research Fund.: Grant number: Erika Bálint, (PD111895).
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List of References
1
Gross, H.; Costisella, B. Angew. Chem. 1968, 80, 364. Angew. Chem. 1968, 7,
391.
2
3
4
Gross, H.; Costisella, B.; L. Haase J. prakt. Chem. 1969, 311, 577-585.
Gross, H.; Costisella, B. J. prakt. Chem. 1969, 311, 925-929.
Gross, H.; Costisella, B. Angew. Chem. 1968, 80, 445-446. Angew. Chem. 1968,
7, 463.
5
6
Gross, H.; Costisella, B. J. prakt. Chem. 1969, 311, 563-570.
Keglevich, G.; Bálint, E.; Kiss, N. Z. The use of MW in organophosphorus
chemistry. In: Milesstones in Microwave Chemistry – SpringerBriefs in Molecular
Science, Ed.: Keglevich, G.; Springer, Switzerland, 2016, Ch.3, 47-76.
a) Bálint, E.; Tajti, A.; Dzielak, A.; Hägele, G.; Keglevich, G. Beilstein J. Org.
Chem. 2016, 12, 1493-1502. b) Tajti, A.; Tóth, R. E.; Kalocsai D.; Keglevich, G.;
Bálint, E. Phosphorus, Sulfur Silicon Relat. Elem. 2016, 191, 1541-1542.
a) Hägele, G. Habilitation, „Kernresonanzspektroskopische Untersuchungen an
Organo-Phosphor und -Fluor-Verbindungen“. Heinrich-Heine-University
Düsseldorf, 1972. b) Hägele, G.; Harris, R. K.; Nichols, J. M. J. Chem. Soc.
Dalton Trans. 1973, 79-82. c) Hägele, G.; Tossing, G.; Kückelhaus, W.; Seega,
J.; Harris, R. K. J. Chem. Soc. Dalton Trans. 1984, 2803-2812. d) Hägele, G.;
Kückelhaus, W.; Tossing, G.; Mootz, D.; Wussow, H. G. Phosphorus and Sulfur
1985, 22, 241-246.
7
8
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9
Kashemirov, B. A.; Bala, J. L. F.; Chen, X.; Ebetino, F. H.; Xia, Z.; Russell, R. G.
G.; Coxon, F. P.; Roelofs, A. J.; Rogers, M. J.; McKenna, C. E. Bioconjugate
Chem. 2008, 19, 2308-2310.
10
TOPSPINTM 3.5 pl6, Bruker BioSpin GmbH, Rheinstetten, Germany, 2016.
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Table 1: NMR data for the methoxy region of a 100 MHz 1H NMR spectrum from Me2N-
CH[P(O)(OCH3)2]2 5 (in CDCl3). Solution 1: Results from grid net search for parameters
LAX, LMX and JXX with step widths of 0.25 Hz. H* = relative resonance frequency [Hz] if
the center of methoxy region (A+M)/2 is defined to 0 Hz. Spectral half width is set to
0.25 Hz. An alternative is found with solution 2.
Parameter
Solution
N
[Hz]
L
[Hz]
3JPH
[Hz]
5JPH
[Hz]
2JPP
[Hz]
H*
[Hz]
1
1
+0.50
-0.50
11.00
11.10
5.25
6.25
8.13
8.68
2.88
2.43
16.25
16.25
POCH3 (I) A3
POCH3 (II) M3
2
2
+0.50
-0.50
11.00
11.10
9.2
10.1
10.1
10.6
0.9
0.5
60
60
POCH3 (I) A3
POCH3 (II) M3
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Table 2: NMR Parameters δP, 2JPP, N, and 2JPH of Me3N+-
CH[P(O)(OMe)2][P(O)(OMe)O-] 6 (in CDCl3), obtained from: a) proton decoupled 31P{1H}
and b) from proton-coupled 36.4 MHz 31P NMR spectra. The geminal coupling 2JPP
-
close to zero - is not resolved (n. r.).
P
δP
2JPP
3JPH
2JPH
Parameter
[ppm]
[Hz]
[Hz]
[Hz]
a)
b)
X
Y
15.36
-1.20
n. r.
n. r.
11.2
11.3
-22.3
-15.5
P(O)(OCH3)2
P(O)(OMe)O-
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Table 3: 500 MHz 1H NMR data for achiral bisphosphonates 7 and 8 (in CDCl3).
Fragment
Parameter
Compound
7
8
NCHP2
δH
4.2413
-23.9.
4.6470
-25.9
[ppm]
[Hz]
2JPH
POCH3 (I)
POCH3 (II)
δH(A3)
NAX
3.7965
10.8
9.8 – 10.8
10.3 – 10.8
0 – 0.5
3.7721
11.1
10.1 - 11.1
10.6 - 11.1
0 - 0.5
[ppm]
[Hz]
[Hz]
[Hz]
[Hz]
LAX
3JPH
5JPH
δH(M3)
NMX
3.8149
10.8
9.8 – 10.8
10.3 – 10.8
0 – 0.5
3.7867
11.1
10.1 - 11.1
10.6 - 11.1
0 - 0.5
[ppm]
[Hz]
[Hz]
[Hz]
[Hz]
LMX
3JPH
5JPH
2JPP
60 ± 5
60 ± 5
[Hz]
N-CH3
δH
-
-
3.1610
0.9
[ppm]
[Hz]
4JPH
C6H5-N
δH(ortho)
δH(meta)
δH(para)
6.7016
7.2037
6.7994
6.8634
7.2579
6.8174
[ppm]
[ppm]
[ppm]
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Table 4: 125 MHz 13C NMR data for achiral bisphosphonates 7 and 8 (in CDCl3).
Fragment
N-CH3
Parameter
Compound
7
-
8
δC
35.95
[ppm]
NCHP2
δC
50.10
147.8 Hz.
56.62
146.2
[ppm]
[Hz]
1JPC
POCH3 (I)
POCH3 (II)
C6H5-N
δC
Nc
53.85
5.8
53.49
6.4
[ppm]
[Hz]
δC
NC
54.29
5.6
53.70
5.8
[ppm]
[Hz]
δC(ortho)
δC(meta)
δC(para)
δC(ipso)
113.80
129.47
119.43
145.91
4.0
113.98
129.34
118.89
149.66
3.3
[ppm]
[ppm]
[ppm]
[ppm]
[ppm]
3JPC(ipso)
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1
a)
Table 5: 500 MHz H NMR parameters for chiral bisphosphonates 9 and 10. HW =
b)
c)
4.0 Hz;
HW = 1.5 Hz;
HW = 2.0 Hz; br: broad lines; n.r.: not resolved. Spin
assignments were confirmed by HSQC and H,H COSY spectra.
9
10
Fragment
Parameter
Ph-CH(CH3)-N
δH
1.3757
6.6
1.2429
n.r. br
[ppm]
[Hz]
3JHH
C-N(CH3)-C
NCHP2
δH
2.7389
-
[ppm]
δH
3.6868
26.54
24.32
3.6928
n.r.
n.r.
[ppm]
[Hz]
2JPH
2JPH
POCH3 (I)
δH
3.7089
10.8
3.6510
10.4
[ppm]
[Hz]
3JPH
POCH3 (II)
POCH3 (III)
POCH3 (IV)
Ph-CH(Me)-N
δH
3.7616
10.8
3.6717
10.2
[ppm]
[Hz]
3JPH
δH
3.8220
10.8
3.7066
10.7
[ppm]
[Hz]
3JPH
δH
3.8335
10.8
3.7269
10.6
[ppm]
[Hz]
[Hz]
[ppm]
[Hz]
3JPH
δH
4.1148
6.6
4.3528
n.r. br
3JHH
4JPH
3.2
N-CH2-Ph
δH(HA)
δH(HB)
2JHH
-
-
-
4.4063
4.1663
-15.0
[ppm]
[ppm]
[Hz]
Ph-CH2-N
δH(ortho)
δH(meta)
δH(para)
-
-
-
7.5136 a br
7.3195 b
7.2226 c
[ppm]
[ppm]
[ppm]
Ph-CH(CH3)-N
δH(ortho)
7.3503
7.3731 a br
[ppm]
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δH(meta)
δH(para)
7.3089
7.2447
7.3011 b
7.2189 c
[ppm]
[ppm]
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Table 6: 125 MHz C NMR data for chiral bisphosphonates 9 and 10. br: broad lines.
Spin assignments were confirmed by HSQC and H,H-COSY spectra.
Fragment
Parameter
Compound
9
10
Ph-CH(CH3)-N
N-CH3
δC
22.14
20.04 br
[ppm]
δC
37.66 br
3.0 d
-
-
[ppm]
[Hz]
3JPC
POCH3 (I)
POCH3 (II)
POCH3 (III)
POCH3 (IV)
δC
52.81
7.0
53.16
6.3
[ppm]
[Hz]
2JPC
δC
53.04
6.9
52.93
6.4
[ppm]
[Hz]
2JPC
δC
53.06
6.8
52.93
6.4
[ppm]
[Hz]
2JPC
δC
53.64
6.9
52.66
6.1
[ppm]
[Hz]
2JPC
C6H5-CH2-N
NCHP2
δC
-
54.80 br
δC
56.33 dd
148.8
136.4
55.55 t
143.3
143.3
[ppm]
[Hz]
[Hz]
1JPC
1JPC
C6H5-CH(CH3)-N
C6H5-CH(CH3)-N
δC
64.08
3.3
9.1
61.71 br
n.r.
[ppm]
3JPC
3JPC
n.r.
δC(ortho)
δC(meta)
δC(para)
δC(ipso)
127.8664
128.5241
127.4960
144.5736
128.11
128.28
127.31
143.95
[ppm]
[ppm]
[ppm]
[ppm]
C6H5-CH2-N
δC(ortho)
δC(meta)
δC(para)
-
-
-
128.23 br
128.37 br
126.62 br
[ppm]
[ppm]
[ppm]
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δC(ipso)
-
141.82 br
[ppm]
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O
CH3O
Me2N
CH3O
P
C
P
O
OCH3
H
A3
X
M3
OCH3
A3´
X´
M3´
Figure 1: [A3M3X]2 spin system for the [P(O)(OCH3)2]2 fragment of compound 5.
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Figure 2: Methoxy region of the 100 MHz 1H NMR spectrum of Me2N-CH[P(O)(OCH3)2]2
5 in CHCl3. Left: experimental. Right: simulated solution 1 with parameters shown in
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7
8
Figure 3: Methoxy regions in 500 MHz 1H NMR spectra of 7 (upper) and 8 (lower).
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Figure 4: 500 MHz 1H NMR spectrum of a fresh solution of 7 in CDCl3. ABMX2
approximation for the HNCHP2 part of 7. Iterated parameters: δH(CH) = 4.244 ppm.
δH(NH) = 4.146 ppm. 3JHH = 8.9 Hz. 2JPH = -22 Hz. 3JPH = 2 Hz. Spectral half widths:
HW(CH) = 3.4 Hz. HW(NH) = 11.0 Hz.
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Figure 5: Methoxy region of the 125 MHz 13C{1H} NMR spectra. of compounds 7-10.
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9
10
Figure 6: 202 MHz 31P{1H} NMR spectra of compounds 9 and 10 (in CDCl3). Upper: 9.
Lower: 10, a stronger coupled XY system with line broadening for PY in high field
resonances.
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O
CH3O
Ph-CH(Me)-(Me)N
CH3O
P
C
P
O
OCH3
H
A3
X
Y
G3
T3
OCH3
M3
Figure 7: A3G3M3T3XY spin system for [P(O)(OCH3)2]2 fragment of compound 9.
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