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7.5^ 7.0^ 6.5^ 6.0^ 5.5^ 5.0^ 4.5^ 4.^
3.5^ 3.0^ 2.5^ 2.0^ 1.5^ 1.0^ 0.5^0 Chemical Shift (ppm)500 MHz, CDCl
3
5H 1H^ 2H^ 2H^ 2H
4 Me^11810 Si^53 O^12926 ONPh 17 O O^ 2H 1H^ 3H^ 4H^ 9H^ 6H
5H^ 1H^ 2H^ 3H^ 2H
Chem 106 2H 3H 4H 9H 6H
E. Kwan^ Problem 1^ The addition of lithium dimethylcuprate to an alkyne produced a mixture of
E^ and^ Z^ isomers which were separated by HPLC. Please assign the resonances in the spectra below and determine which isomer is which.
NMR III
4.0^ 3.5^ 3.^
2.5^ 2.0^ 1.^
Chemical Shift (ppm)
2.81.12.01.01.11. 1.01.01.02.0 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16
8 0 13.9125.2727.1042.2046.1448.3559.84173.99 Chemical Shift (ppm) Chem 106 E. Kwan^ Problem 2^ Please assign the proton and carbon resonances of ethyl nipecotate. (500 MHz, CDCl
; spectra are courtesy of 3 Dr. Jeffrey Simpson, MIT. See Simpson, Chapter 9 for his treatment of this problem.)O O NH
NMR III
4.0^ 3.5^ 3.0^ 2.^
Chem 106^10152025303540 F1 Chemical Shift (ppm)^45505560 2.0 1.5 1.0F2 Chemical Shift (ppm) E. Kwan^ Problem 2 O O^ NH
NMR III This is the HMQC spectrum. Please number the protons. What are the methylene pairs in thismolecule? Are there any quaternary carbons?
Chem 106 E. Kwan^ Problem 2 O O^ NH
NMR III This is the COSY spectrum. Try to label the off-diagonal peaks. 4.0 3.5 3.0^ 2.5^ 2.0^ 1.5^ 1.0F2 Chemical Shift (ppm)
1.0 1.5 2.0 2.5 F1 Chemical Shift (ppm)3.0 3.5 4.
5.2^ 5.1^ 5.0^ 4.9^ 4.8^ 4.7^ 4.6^ 4.5^ 4.4^ 4.3^ 4.2^ 4.^
Chem 106^5860 inset^626064616662686370647265746676677868 F1 Chemical Shift (ppm)F1 Chemical Shift (ppm) (^698070827184728688) 3.65 3.60 3.55 3.50 3.45 3.40 3.35 3.30F2 Chemical Shift (ppm)^9092 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3^ 3.2F2 Chemical Shift (ppm) E. Kwan^ Problem 3^ Please assign the proton and carbon resonances of sucrose (500 MHz,
NMR IIID^ O^ ).^2 arrows: doubleintensity^ HMQC
5.2^ 5.1^ 5.0^ 4.9^ 4.8^ 4.7^ 4.6^ 4.5^ 4.4^ 4.3^ 4.2^ 4.^
Chem 106 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4.0 4.1 4.2 4.3 4.4F1 Chemical Shift (ppm)4.5 4.6 4.7 4.8 4.9 5.0 5.1 5.2 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3F2 Chemical Shift (ppm) E. Kwan^ Problem 3
NMR III COSY-
Chem 106 E. Kwan^ Problem 4
NMR III An unknown compound of molecular weight 348 has the spectral data shown below.^ A singlet near3.2 ppm disappears on D 2 O addition. Please deduce its molecular formula, skeletal connectivity,assignments, and relative stereochemistry (show key ROESY correlations). 113 ID Hs Type J (Hz) COSY Key HMBC^ Key ROESY (H) (C) 1 5.20 73.1 1 t 9.5x2 3, 2 170.4^ 4, 7 2 5.08 68.7 1 t 9.5x2 1, 7 169.6^3 3 4.96 71.6 1 dd 9.5, 8.0 4, 1 169.4^2 4 4.59 99.8 1 d 8.0 3 1, 7 5 4.26 62.3 1 dd 12.3, 4.9 6, 7 170.8^7 6 4.11 62.3 1 dd 12.3, 2.5 5, 7 170.8^7 7 3.68 71.8 1 m -- 2, 5, 6 1, 4, 5, 6 8 ~3.2 -- 1 br s -- -- 9 2.08 20.95 3 s -- -- 170.8 10 2.05 20.90 3 s -- -- 169.4 11 2.02 20.79 3 s -- -- 169.6 12 2.00 20.83 3 s -- -- 170.4Quaternary Carbons: 170.8, 170.4, 169.6, 169.4 Molecular formula:
Chem 106 E. Kwan^ Problem 5
NMR III O OMeKHMDS?OOTHF, rt^ LR-ESI-MS: 389.2 OTBSNOO Please deduce the flat structure of the byproduct.Please deduce the structure and relative stereochemistry of the product. NMR Data (500 MHz, 45% CDCl in C D ) 3 66 113 ID Hs Type J (Hz) COSY-45^ Key HMBC^ NOE (H) (C) 1 5.66 131.5 1 m -- 2, 3, 4 2 5.13 119.0 1 dd 17.1, 1.5 1, 3, 4 3 5.02 119.0 1 dd 10.5, 1.2 1, 2 4 4.39 66.1 2 m -- 1, 2 119.0, 131.5, 168.2 5 3.80 56.6 1 d 2.4 10 41.3, 43.9, 71.2, 168.2, 200.5^11 6 3.61 71.2 1 dd 9.0, 3.2 9, 11 56.6^10 7 3.10 63.2 1 t 2.9x2 9, 11 71.2, 200.5, 203.4 8 2.81 43.9 1 d 19.5 10 20.5, 41.3, 56.6, 203.4 9 1.94 34.2 1 ddd 14.6, 9.3, 2.9 6, 7, 11 63.2, 200.5 10 1.76 43.9 1 dd 19.5, 2.0 5, 8 20.5, 41.3, 56.6, 71.2, 203.4^6 11 1.52 34.2 1 dt 14.6, 2.9x2 6, 7, 9 71.2, 203.4^5 12 0.94 20.5 3 s -- -- 41.3, 43.9, 56.6, 71.2 13 0.81 25.9 9 s -- -- 25.7 14 -0.10 -4.5 6 d -- -- -- Quaternary Carbons: 200.5, 203.4, 168.2, 41.3, 25.7; IR: three carbonyls present
7.5^ 7.0^ 6.5^ 6.0^ 5.5^ 5.0^ 4.5^ 4.^
3.5^ 3.0^ 2.5^ 2.0^ 1.5^ 1.0^ 0.5^0 Chemical Shift (ppm)500 MHz, CDCl
3
5H 1H^ 2H^ 2H^ 2H
4 Me^11810 Si^53 O^12926 ONPh 17 O O^ 2H 1H^ 3H^ 4H^ 9H^ 6H
5H^ 1H^ 2H^ 3H^ 2H
“normal” allylicproton shift E isomerallylic proton:downfield due toA(1,3) strainZ isomer^ 2H^ 3H^ 4H^ 9H^ 6H
By far the simplest spectrum to understand, begin here.
COSY^ axes:^ proton, proton^ correlations:^ off-diagonal peaks are 2-3 bond couplings between protons^ purpose:^ assign protons to spin systems^ spin system:^ a set of protons sharing through-bond ( J ) couplings^41 O^25 63 1-2-3, 4-5, 6
- HSQC: 1-bond C,H2. COSY: 2,3-bond H,H3. HMBC: 2,3-bond C,H HSQC axes:^ proton, carbon correlations:^ 1-bond C,H couplings purpose:^ number proton spectrum, match each proton with a carbon, identifyCHpairs^2 12 3 down (CH)^2 up (CH, CH)^3 Bcarbon A protonproton 1 is^ directlyattached^ to carbon A Numbering the Spectrum^ Even if the proton spectrum overlaps, HSQC will usually separate the peaksenough so they can be numbered (convention: left to right).^1 2,3^4 - although 2 and 3 overlap inthe 1D spectrum, they have^42 very different carbon shiftsCcarbonso the HSQC separates themB^3 A^1 proton
Chem 117 Next, use COSY to determine the composition of each spin system.- all experiments are proton-detected A B C D D protonC B A protons 2 and 3 are on theA-B-C, D same carbon ; i.e., 2/3 isa methylene (CH) pair 2 proton HMBC axes: proton, carbon correlations: 2-3 bond couplings between protons purpose: connect spin systems 12 one-bond artifact: proton 2 is directlyattached to carbon Bcarbon(look for doublets)B A- only give a number for eachunique chemical shift (e.g.,a methyl group only gets one protonnumber)proton 2 is 2 or 3 bondsaway from carbon Aproton 1 is 2 or 3 bondsaway from carbon A
E. Kwan^ Lecture 8: Solving Structural Determination ProblemsSummary of 2D NMR Experiments
xx^ xx^4 51 13 ID (H) (C) Hs^ type^ J^ (Hz)^ COSY^ HMBC 1 5.76 145.23 1 d^ 5.1^2 152.12 2 3.76 72.45 1 d^ 5.1^ 1,3^ 32.47 3 3.47 -- 1 br s^ --^ --^ 202.57... etc ... Quaternary Carbons:^ 35.57, 54.32, 202.57... CH pairs: 4/5, ... (^2) - peaks are listed by number from high to low chemical shift- HSQC: connect each proton to its directly attached carbons;find methylene pairs- COSY: if 1 is coupled to 2, then check that 2 is coupled to 1;however, both partners of a methylene pair may not showcouplings to a common partner (peak 3)- exchangeable protons do not appear in the HSQC- quaternary carbons can be found from HMBC or the 1Dspectrum carbon- HMBC: watch for one-bond peaks; more intense peaks likemethyl groups are more likely to show long-range correlations; (^2 23) sp systems: J is small, but^ J^ is large (bigger for anti than syn)
Chem 117
E. Kwan^ Lecture 8: Solving Structural Determination ProblemsWorkflow(2) Tabulate Data^ (d) Multiplicity4/5 is a methylene pair.(g) Bookkeeping: Here is the format I use. A similar format isused in many natural products papers.
(3) Generate Spin Systems^ - Use COSY to build up spin systems. Each "component" ofthe spin system is a methyl group, a methylene pair, or amethine (from the HSQC). Double-headed arrows represent(putative) vicinal couplings, with dashed lines for long-rangecouplings:^6 7 4/5^8 1 23^ long-range coupling^ (You might not know which ones are long-range. Use yourchemical intuition and look at the peak intensities andasymmetry about the diagonal. You might have to changeyour diagram if you find it to be inconsistent later.) (4) Connect Spin Systems^ Look for HMBC correlations that connect a proton in onespin system to a carbon in another spin system :^ 33.37^ 145.23^8 3 4/5^1 6 72 Curved arrows indicate HMBC correlations. If you find sucha connection, that tells you that the spin systems must beadjacent in the head-to-tail sense shown. Note that thesedo not have to be mutual like COSY couplings:^ H^ H^ H^ H finding thiswill be^ does^ not^ C C^ CC^ C^ C HMBCpresent^ meancorrelation If that doesn't work, you can look for a carbon, possiblyquaternary, that protons in both spin systems have commonHMBC correlations to:^ 35.57^6 73 4/5^8 1
2.0^ 1.^
1.0Chemical Shift (ppm) (^1 2 3 4) 3.45 3.35Chemical Shift (p...^ Chemical Shift (ppm)
exchangeable 5 HO 6 7 8 9-12^ 13 14 2
3.5^ 3.0^ 2.5^ 2.^
16 24 32 40 48 F1 Chemical Shift (ppm) (^566472) 1.5 1.0 0.5F2 Chemical Shift (ppm) 1 2 3
4 5 6 7 8
HMBC - arrows indicate one-bond peaks- these artifacts appear as doublets in proton dimension
Chem 117
E. Kwan^ Lecture 8: Solving Structural Determination ProblemsWorkflow(5) Generate Fragments^ In many cases, complex, overlapping signals will prevent youfrom drawing out all the spin systems of the molecule. Inparticular, unknown structural elucidations will require you togenerate and connect^ fragments , which are tied together bywhat is visible in a spin system and HMBC. Here is how I puttogether menthol, which has some overlapping signals and onecontinuous spin system: Vicinal COSYKey HMBCFragment Structures^ CorrelationsCorrelations^ 2, 25.82^ 11-2^ 2-14^ 11-14^ HHHC^ CHHC^ CH^ HC^ CH^3 33 33 3 11, 21.0014, 16.07 2-814-811-2^ X^ XX^ XX^ XHH 8, 50.12^ Key Evidence - methyls 11, 14: COSY to 2^ - HSQC: 2, 8 = CH- 2: COSY to 8- 11, 14: mutual HMBC- 11, 14: HMBC to 2, 8- HMBC: double-headed arrows to indicate mutual correlations;single-headed arrows to indicate a one-way correlation- if you feel comfortable, you can write "11-2" instead of "11-25.82" to speed things up, but remember, HMBC correlationsare from protons to carbons- Xs represent non-protons^ Write down your reasoning (even though it's boring).^ Bytheir nature, these problems are very complicated, and there's a99.9% chance you will not remember what peak is at 16.07 ppmseveral years from now. If you write down what you werethinking, you and others will be able to follow your process lateron without repeating the entire analysis. It's also likely you willmake some mistakes, which will be easier to track down this way.
(6) Entry Points^ When you look at a COSY or HMBC spectrum, you will see alot of peaks. Where should you start generating fragmentsfrom? In general: clearly resolved peaks with unambiguousor characteristic chemical shifts. Here are some ideas:- carbonyl region^ - aromatic rings and olefins- methyl groups^ - quaternary carbons (7) Expand and Connect Fragments^ Don't bite off too much at a time. Make a small fragment withcorrelations you feel confident in assigning. Then, move onto another entry point and generate another fragment.Fragments with uncertain correlations are hard to use. Onceyou have exhausted all the easy data, work on what's left toexpand your existing fragments, and if possible, connect them.XHOHO^ 5-13, 9-4 CHX^2 6^ 4, 13, 34.51 CH^3 12, 22.10^ - COSY, HMBC correlationsconnect termini^ (8) List Full Assignments^ This is self-explanatory:^214 21.00^11 16.0725.8250.12HO^7 HO^1 5, 9^8 23.1071.534, 13^6 3, 10^ 34.5145.03^ 31.62^12 22.10You should also file all the FIDs and your "good" notes of whatyou've done in the same place. If you feel the compound will gointo your thesis, take the time to write it out in journal format.
