Ulipristal acetate NMR

Ulipristal acetate

(8S,11S,13S,14R,17R)-17-Acetoxy-11-[4-(dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione

EMA:Link, US FDA:link

REVIEW.http://www.fsrh.org/pdfs/ellaOneNewProductReview1009.pdf

126784-99-4 CAS

http://www.google.com.br/patents/US5929262

CA2216737A1, EP0817793A2, WO1996030390A2, WO1996030390A3

1. The United States Of America As Represented By The Department Of Health And Human Services

m.p. 183-185

IR

1735 and 1714(--C═O), 1664 and 1661 (conjugated --C═O), 1563, 1518, 1441, 1351, 1305, 1252, 1203, 1171;

NMR (CDCl.sub.3)

δ0.38 (s, 18-CH.sub.3),

2.10 (s, 17-OAc),

2.14 (s, 21-CH.sub.3),

2.92 (s, --N(CH.sub.3).sub.2,

4.44 (d, C-11 H),

5.83 (br. s, C-4 H),

6.71 and 7.07 (d, aromatic H);

MS(EI) m/z (relative intensity) 475(M.sup.+, 41), 134(18), 121 (100).

Analysis calculated for C.sub.30 H.sub.37 NO.sub.4 : C, 75.76; H, 7.84; N, 2.94. Found. C, 75.80; H 7.96; N, 3.09.

http://newdrugapprovals.org/2014/04/07/ulipristal-acetate-for-emergency-contraception/

4-methoxyphenyl methanol, (4-メトキシフェニル)メタノール NMR, IR , MASS

(4-methoxyphenyl)methanol

Structure: 

IUPAC Name: 4-methoxyphenyl methanol

C₆H₁₀O₃; MW = 138.17

The molecule contains two oxygens, and from the analysis, contains four double bonds, carbonyls or rings. The large number of degrees of unsaturation strongly suggests an aromatic compound (DU = 4).

The mass spectrum displays a molecular ion, which is the base peak, an m-1 and an m-17, all of which are consistent with a simple alcohol.

The ¹³C spectrum contains six peaks, indicating that the molecule has some elements of symmetry. The quartet at  56 and the triplet at  71 represent a CH₃ and a CH₂ group which are deshielded by electronegative atoms (most likely oxygen); the peaks at  161 - 128 are in the aromatic region; the fact that two doublets and two singlets are observed strongly suggests 1,4-disubstitution.

The proton NMR also shows evidence for aromatic 1,4-disubstitution and suggests that the methyl and methylene are isolated and adjacent to electronegative groups. A peak consistent with an alcoholic OH can also be seen.

The IR is consistent with an aromatic alcohol containing no carbonyl group, suggesting that the second oxygen is involved in an ether linkage.

The simplest structure which is consistent with all of these data would be an aromatic compound containing an alcohol group and a methyl ether, situated 1,4 relative to each other.

IH NMR

The proton NMR has two doublets at  6.9, consistent with aromatic 1,4-disubstitution, and three singlets, areas 3, 2 and 1. The singlets at  3.6 and 4.7 are highly shifted and suggest isolated CH₃ and CH₂ groups adjacent to one or more electronegative atoms or groups. The singlet, area 1, would be consistent with an alcohol.

Predict NMR spectrum

13C NMR

The ¹³C spectrum contains six peaks, indicating that the molecule has some elements of symmetry. The quartet at  56 and the triplet at  71 represent a CH₃ and a CH₂ group which are deshielded by electronegative atoms (most likely oxygen); the peaks at  161 - 128 are in the aromatic region; the fact that two doublets and two singlets are observed strongly suggests 1,4-disubstitution.

¹³C NMR Data: q-56.0; t-71.0; d-114.3; d-128.3; s-160.9; s-133.2

¹³C NMR Assignments: 

MASS

The mass spectrum consists of a molecular ion at 138, which is also the base peak, an m-1 peak at 137, indicating the presence of a labile hydrogen (OH or CHO), and an m-17 peak (loss of HO-). The spectrum is consistent with an alcohol which cannot readily break down to form other stable radical cations.

Mass Spectrum Fragments: 

IR

3400-3200 cm^-1: strong OH peak 3100 cm^-1: small peak, suggesting possible unsaturated CH 2900 cm^-1: strong peak suggesting saturated CH 2200 cm^-1: no unsymmetrical triple bonds 1710 cm^-1: no carbonyl 1610 and 1500 cm^-1: sharp peaks, consistent with aromatic carbon-carbon double bonds

Synthetic Communications, 18, p. 613, 1988 DOI: 10.1080/00397918808064019
Synthesis, p. 1081, 1984
Tetrahedron Letters, 32, p. 3243, 1991

Diethyl benzylmalonate, IR, NMR, Mass

The mass spectrum displays a molecular ion, an m-45 and a peak at m/e = 91, all of which are consistent with a molecule containing benzyl and ethoxy groups.

The ¹³C spectrum contains six peaks, indicating that the molecule has some elements of symmetry. The quartet at  56 and the triplet at  71 represent a CH₃ and a CH₂ group which are deshielded by electronegative atoms (most likely oxygen); the peaks at  161 - 128 are in the aromatic region; the fact that three doublets and one singlet are observed strongly suggests monosubstitution.

The proton NMR also shows evidence for two ethyl groups, a CH-CH₂- group, and a monosubstituted aromatic group; the chemical shift suggests that the carbons of the CH-CH₂- adjacent to one or more electronegative groups.

The IR is consistent with an aromatic compound containing a carbonyl group.

The simplest structure which is consistent with all of these data would be an aromatic compound linked via a -CH₂CH group to a diethyl ester.

Structure: 

IUPAC Name: ethyl ethyl benzylpropanedioate (diethyl benzylmalonate)

607-81-8

C₁₄H₁₈O₄; MW = 250.29

1H NMR

The proton NMR has a coupled quartet and a triplet, consistent with an ethyl group in which the CH₂ (at  4.1) is adjacent to an electronegative atom (most likely oxygen). The presence of a coupled triplet and doublet suggests the presence of a CH-CH₂- group in which both carbons are adjacent to one or more electronegative atoms. The singlet at  7.1 is consistent with a monosubstituted aromatic compound.

13C NMR

The ¹³C spectrum contains nine peaks, indicating that the molecule has some elements of symmetry. The quartet at  14 and the triplet at  60 represent a simple CH₃ and a CH₂ which is deshielded by an electronegative atom (most likely oxygen); the doublet at  58 and the triplet at  36 are CH and CH₂ groups which are adjacent to one or more electronegative groups. The peaks at  141 - 125 are in the aromatic region; the fact that three doublets and one singlet are observed strongly suggests monosubstitution.

¹³C NMR Assignments: 

MASS

The mass spectrum consists of a molecular ion at 250, a base peak at 91 (a benzyl group), an m-45 peak at 205, indicating the presence of an ethoxy group; other significant peaks at 131 and 176 must be consistent with the proposed structure. The spectrum is consistent with a molecule containing ethoxy and benzyl groups.

Mass Spectrum Fragments: 

IR

3400-3200 cm^-1: no OH peak 3100 cm^-1: small peak, suggesting unsaturated CH 2900 cm^-1: strong peak suggesting saturated CH 2200 cm^-1: no unsymmetrical triple bonds 1730 cm^-1: strong carbonyl 1610 and 1500 cm^-1: weak peaks, vaguely consistent with aromatic carbon-carbon double bonds

ADDITIONAL INFO FOR READER ON SPECTROSCOPY

SEE THE FUN WHEN A CARBONYL IS INTRODUCED

1H NMR

13 C NMR

IR

MASS

RAMAN

Sucrose 2D NMR Spectra

The sugar sucrose can be used to illustrate  homonuclear 2D NMR experiment: the TOCSY.

Sucrose

Table sugar

Sucrose ("table sugar") is a disaccharide derived from glucose and fructose.

The interesting element from an NMR spectroscopy viewpoint is that the two monomer units are completely separate spin systems and this can be visualised in the TOCSY spectrum.

HH COSY

The HH COSY shows the coupling network within the molecule.

HH TOCSY

The HH TOCSY spectrum shows correlations that belong together in contiguous spin systems: in the sucrose example, this means that the protons in the respective glucose and fructose units can be assigned.

HMQC

In the HMQC spectrum the one-bond direct HC couplings can be viewed as cross-peaks between the proton and carbon projections.

HMBC

2D NMR spectroscopy for the structural elucidation of 4.

A multistep single-crystal-to-single-crystal bromodiacetylene dimerization

http://www.nature.com/nchem/journal/v5/n4/fig_tab/nchem.1575_F6.html

• Tobias N. Hoheisel,
• Stephen Schrettl,
• Roman Marty,
• Tanya K. Todorova,
• Clémence Corminboeuf,
• Andrzej Sienkiewicz,
• Rosario Scopelliti,
• W. Bernd Schweizer
• & Holger Frauenrath

Nature Chemistry5,327–334(2013) 

doi:10.1038/nchem.1575

The heteronuclear multiple bond correlation NMR spectrum (400 MHz, CDCl3) of dimer 4 with the corresponding 1D ¹H NMR and ¹³C NMR traces exhibited ten acetylene carbon resonances, a duplication of the propargyl methylene proton resonances that coupled with four and six acetylene carbons, respectively, as well as two new olefin carbon resonances that coupled only with the propargyl methylene protons on the ‘shorter’ side of the molecule. The inset is a magnified view of the region of the acetylene cross-peaks. For a more detailed discussion, see the Supplementary Information.

SEE

http://www.nature.com/nchem/journal/v5/n4/extref/nchem.1575-s1.pdf

1H-1H COSY NMR

¹H-¹H COSY (COrrelated SpectroscopY) is a useful method for determining which signals arise from neighboring protons (usually up to four bonds). Correlations appear when there is spin-spin coupling between protons, but where there is no coupling, no correlation is expected to appear.

This method is very useful when the multiplets overlap or when is extensive second order coupling complicates the 1D spectrum.

There are many variants on the COSY pulse sequence. The most popular one in our laboratory is the gradient enhanced double quantum coherence (DQF-COSY) version. The ratio of gradient strengths is usually set to two to yield all COSY signals but may be set to three to yield only those correlations involving three protons, e.g., CH-CH₂. We use the gradient enhanced DQF-COSY pulse sequence shown in fig. 1.

Fig. 1. Pulse sequence for gradient DQF-COSY

The COSY spectrum as shown in fig. 2 for ethylbenzene (fig. 3) contains a diagonal and cross peaks (signals that are not on the diagonal and correspond to other signals on the same horizontal and vertical projections). The cross peaks indicate couplings between two mutliplets up to three, or occasionally four, bonds away. The diagonal consists of the 1D spectrum with single peaks suppressed.

The most apparent cross-peak in the spectrum is between H1' and H2' at 2.65 and 1.24 ppm. A much weaker four-bond correlation (see the figure below) appears between H1' and H2 at 2.65 and 7.20 ppm. All the desired signals are antiphase. Half the multiplet is positive and half negative. In addition, artifacts (undesired signals) appear in the spectrum as vertical streaks (interference and f₁ noise) and along the inverted 'V' (fig. 4) whose tip is on the top axis of the sepctrum. These artifacts are rarely in phase with the desired signals and appear in specific locations.

Fig. 2. 2D COSY spectrum of ethylbenzene

Fig. 3. Structure of ethylbenzene

Fig. 4. Artifacts in the COSY spectrum of ethylbenzene

For example, in 12,14-di^tbutylbenzo[g]chrysene (fig. 5), only a partial analysis of the regular ¹H-NMR spectrum is possible. COSY (fig. 6) provides extra information about the connectivity. No correlations (cross-peaks) are seen to the tbutyls because they are too many bonds away from the ring system.

Fig. 5. Structure of 12,14-di^tbutylbenzo[g]chrysene

Fig. 6. Artifacts in the COSY spectrum of ethylbenzene

The aromatic region of the spectrum (fig. 7) shows three bond correlations strongest. These can be used to determine which protons are neighbors. For example the proton at 8.17 ppm is next to the proton at 7.34 ppm, a fact that could not be easily determined from the 1D spectrum.

Fig. 7. Aromaric region of the 2D COSY spectrum of 12,14-di^tbutylbenzo[g]chrysene showing mostly three-bond correlations (a four-bond correlation between H10 and H11 is also visible)

Four-bond and five-bond correlations are apparent when plotted to lower contours (fig. 8). These separate the spectrum into four groups of protons in a manner that is much clearer than the 1D spectrum.

Fig. 8. Aromaric region of the 2D COSY spectrum of 12,14-di^tbutylbenzo[g]chrysene showing three, four and five-bond correlations

Using horizontal and vertical lines, it is possible to separate each group and follow its connectivity (fig. 9). The blue group of four protons is connected in the order 8.62 ppm to 7.55 to 7.59 to 8.56, the green group of four protons in the order 8.54 to 7.34 to 7.44 to 8.17 and the red group or two protons, that correspond to H9 and 10 because they are the only group of two protons expected to have a three-bond coupling constant (8.9 Hz), are at 7.76 and 8.32 ppm. The yellow group of two protons correspond to H11 and 13 because the coupling constant is small (1.9 Hz) and consistent with a four bond correlation.

Fig. 9. Aromaric region of the 2D COSY spectrum of 12,14-di^tbutylbenzo[g]chrysene showing connectivity and separation into four color-coded proton groups

The multiplet structures in COSY are anti-phase for active couplings which leads to different patterns that for pure phase. A pure singlet (A) will not appear in a DQF-COSY spectrum because it is purely single quantum and a double-quantum filter is applied. This is true for deuterated solvent signals and for some protiated solvents such as water. Advantage of this is often taken for solvent suppression. A simple doublet appears in anti-phase. Many other combinations exist. The more common ones are listed in the table below and a few examples are shown.

Table 1. multiplicities often seen in COSY spectra compared with their pure phase counterparts.^a

Multiplicity	Pure phase	Anti-phase
A	1	0
AX	1 1	1 -1
AX2	1 2 1	1 0 -1
AXY	1 1 1 1	1 1 -1 -1
AYX	1 1 1 1	1 -1 1 -1
AX3	1 3 3 1	1 1 -1 -1
AX2Y	1 2 1 1 2 1	1 0 -1 1 0 -1
AY2X	1 2 1 1 2 1	1 2 1 -1 -2 -1
AXY2	1 1 2 2 1 1	1 -1 2 -2 1 -1
AYX2	1 1 2 2 1 1	1 -1 0 0 1 -1
AYX2, JAY=2JAX	1 2 2 2 1	1 0 0 0 -1
AXYZ	1 1 1 1 1 1 1 1	1 1 1 1 -1 -1 -1 -1
AYXZ	1 1 1 1 1 1 1 1	1 1 -1 -1 1 1 -1 -1
AYZX	1 1 1 1 1 1 1 1	1 -1 1 -1 1 -1 1 -1
AXYZ, JAX=JAY+JAZ	1 1 1 2 1 1 1	1 1 1 0 -1 -1 -1
AXYZ, JAY=JAX+JAZ	1 1 1 2 1 1 1	1 1 -1 0 1 -1 -1
AXYZ, JAZ=JAX+JAY	1 1 1 2 1 1 1	1 -1 1 0 -1 1 -1
AX6	1 6 15 20 15 6 1	1 2 1 0 -1 -2 -1

^aThe active coupling is from A to X. The coupling constant decreases from left to right, e.g., for AXYZ, J_AX > J_AY > J_AZ.

Figs. 10-13 show expansions of COSY multiplets. The red contours are negative and the black ones are positive. The 1D projections are only representations (in practice the sum of the projection is zero).

Fig. 10. Anti-phase AX correlation between doublets H9 and 10 of 12,14-di^tbutylbenzo[g]chrysene

Higher multiplicities in which all the couplings are active yield the patterns shown in table 1. For example the correlation between the CH₃ and CH₂ protons in ethylbenzene yield a 1 0 1 pattern in one direction and a 1 1 -1 – 1 pattern in the other direction (fig. 11).

Fig. 11. Anti-phase A₂X₃ correlation between the ethyl protons of ethylbenzene

When there are more than two multiplets coupled, then only one coupling is active in each cross-peak. This can be used to determine which coupling constant relates to which correlation, something that may not be obvious from the 1D spectrum. In figs. 12 and 13 for di^tbutylbenzo[g]chrysene, the active couplings are labeled. The top cross-peak between the protons at 7.34 and 8.17 ppm shows the largest active coupling of 8.1 Hz. The coupling pattern in the vertical (f₁) direction is 1 1 1 0 -1 -1 -1 and in the horizontal (f₂) direction it is 1 1 1 1 -1 -1 -1 -1. The multiplet below it has the smallest active coupling of 1.4 Hz. The f₁ coupling pattern is 1 -1 1 0 -1 1 -1 and the f₂ coupling pattern is 1 1 -1 -1 1 1 -1 -1. The bottom multiplet displays an active coupling of 7.0 Hz and the coupling pattern in both directions is 1 1 -1 0 1 -1 -1.

Figs. 12, 13. Comparison of three AXYZ correlations showing different active couplings (from the COSY of 12,14-di^tbutylbenzo[g]chrysene)

EXAMPLE

COSY spectra

• The information on the H that are coupling with each other is obtained by looking at the peaks inside the grid.  These peaks are usually shown in a contour type format, like height intervals on a map.
• In order to see where this information comes from, let's consider an example shown below, the COSY of ethyl 2-butenoate 
• First look at the peak marked A in the top left corner.  This peak indicates a coupling interaction between the H at 6.9 ppm and the H at 1.8 ppm.  This corresponds to the coupling of the CH₃ group and the adjacent H on the alkene.
• Similarly, the peak marked B indicates a coupling interaction between the H at 4.15 ppm and the H at 1.25 ppm.  This corresponds to the coupling of the CH₂ and the CH₃ in the ethyl group.
• Notice that there are a second set of equivalent peaks, also marked A and Bon the other side of the diagonal.

The (H,H) COSY experiment establishes the connectivity of a molecule by giving cross peaks (these are the off diagnonal peaks) for pairs of protons that are in close proximity. For the example of Glutamic acid below, we obtain cross peaks for the proton pairs (2,3) and (3,4). We do not observe a crosspeak for the pair (2,4), because these protons are not directly adjacent.

A relayed COSY experiment goes one step beyond a COSY experiment by showing cross peaks not just for pairs of adjacent protons, but for triples as well. As a result, we observe additional cross peaks like the one for the pair 2,4 in Glutamic acid below. Relayed COSY experiments can give cross peaks for protons that are too distant to show coupling in the 1D NMR spectrum.500 MHz H-relayed (H,H) COSY Spectrum of Glutamic acid. 1-D spectra left and top. 10 mg of compound in 0.5 mL of D₂O, 5 mm sample tube, 256 spectra, digital resolution of 2.639 Hz/data point. Total measurement time ca. 3h.

500 MHz H-relayed (H,H) COSY Spectrum of Glutamic acid. 1-D spectra left and top. 10 mg of compound in 0.5 mL of D₂O, 5 mm sample tube, 256 spectra, digital resolution of 2.639 Hz/data point. Total measurement time ca. 3h.

With present hardware and pulse sequences, it is possible to repeat the relay step up to three times. This allows the correlation of of protons that are separated by up to six bonds (d-protons). The relaying nucleus is typically ¹H, but high abundance I =1/2 hetero-elements like ³¹P or ¹⁹F can be used as well.

Strychnine 2D NMR Spectra

The poison strychnine is a molecule that is often used as a standard to test advanced 2D NMR experiments.

Strychnine

An unpleasant molecule that offers interesting 2D NMR spectra

The 1D NMR spectra of strychnine are relatively complicated with several areas of overlapping signals; spectra of this type often benefit from spreading these overlapping signals into a second dimension.

HH COSY

The small and simple molecule, trans-ethyl crotonate is often used to illustrate 2D NMR spectroscopic experiments. 

Ethyl crotonate

A simple molecule often used to illustrate and test NMR experiments.

The molecule was chosen for its simplicity so that the elegance of the NMR spectra might be demonstrated.

The HH COSY shows the coupling network within the molecule: the triplet and quartet of the ethyl group share a cross-peak; the alkene protons can be seen to couple to both each other and the terminal methyl group.

The HH COSY shows the coupling network within the molecule: the triplet and quartet of the ethyl group share a cross-peak; the alkene protons can be seen to couple to both each other and the terminal methyl group.

HH COSY