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Advanced Chemistry Development, Inc. (ACD/Labs)
NMR Workshop
Brent LefebvreNMR Product Manager
European User’s Meeting – Obernai, FranceOctober 23, 2007
2
Application and Technical Notes
Application Application Notes and Notes and Technical NotesTechnical Notes
3
Outline
Secrets of Version 11 Revealed!What’s New in NMR
Automatic Quantitation Using Macros and ChemBasic
Database Searching TipsBe a DB search guru
Macro PossibilitiesMeet “Joe Macro”
Advanced Chemistry Development, Inc. (ACD/Labs)
Secrets of Version 11 Revealed
Brent LefebvreNMR Product Manager
NMR Workshop Topic #1
5
Version 11
What’s New?New development in all productsThis is not a complete listModular products, check your modules
6
1D NMR Processor
Improved Multiplet AnalysisMultiplet Report TemplatesSmarter Integral PositionsMore flexible OverlayWith HNMR or CNMR
Assignment Quality PreviewVerification DiagnosticsCalculation ProtocolSolvent Specific Verification
8
Improved Multiplet Analysis
ASCI Data Set• 30 Samples• Poor S/N• 300 MHz• Pharma type Structures
ASCI-1_A1_25_1D1H HNMR Match Factor: HNMR Structure Purity:
1.95 1.90 1.85 1.80 1.75 1.70 1.65 1.60 1.55 1.50 1.45 1.40Chemical Shift (ppm)
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
0.11
0.12
0.13
0.14
0.15
0.16
0.17
0.18
0.19
0.20
Nor
mal
ized
Inte
nsity
ASCI-1_B2_25_1D1H HNMR Match Factor: HNMR Structure Purity:
1.95 1.90 1.85 1.80 1.75 1.70 1.65 1.60 1.55 1.50 1.45 1.40Chemical Shift (ppm)
0
0.005
0.010
0.015
0.020
0.025
0.030
0.035
0.040
0.045
0.050
0.055
0.060
Nor
mal
ized
Inte
nsity
400400 300300
9
Multiplet Report Templates
Custom TemplatesBased on JournalsOr based on your own requirements
Virtually limitless customization
15
Verification Diagnostics
Minor InconsistencyAssignment is present, error can be dismissed if desired
16
And More…
Calculation ProtocolNow available in 1D NMR Processor
For Predicted or Verified Experimental
Solvent-Specific PredictionAnd VerificationNow possible in 1D NMR Processor
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2D NMR Processor
Faster Spectrum DisplayAutomatically attach 1D to axesAutomatic Gridline CreationREAL Correlation SearchPick picking and gridline countWith 2D Predictor
View Calculation Protocol
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And Much More…
Peak Picking & Gridline CountNo need to add these up manually any more!
Calculation protocol as in 1DFor Predicted or Verified spectra
22
NMR Predictors
Improved Stereo-encodingIntegration of Neural NetworkImproved accuracy – AGAIN!Expanded databasesC-H and C-X coupling predicted and available for trainingHit data highlighting
23
Improved Stereo-Encoding
Flaws existed in old stere-encoding schemeNew scheme is much more robustImproved accuracy results
Different isomers give different results in more cases
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Neural Network Integrated
Neural Nets properly integratedNow default prediction uses hybrid value of Neural Net, Incremental scheme and HOSE code
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Improved Accuracy
No “official” numbers yetSmall datasets only so farNew numbers coming soon!
Should show significant improvement in Proton accuracy…
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Expanded Databases
Year 2003 2004 2005 2006 2007Release Version 7.0 Version 8.0 Version 9.0 Version 10 Version 11# of Chemical Shifts
1,320,000 1,384,000 1,440,000 1,578,505 1,666,199
HNMR Database
Year 2003 2004 2005 2006 2007Release Version 7.0 Version 8.0 Version 9.0 Version 10 Version 11# of Chemical Shifts
1,850,000 2,017,000 2,160,000 2,351,827 2,430,218
CNMR Database
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Structure Elucidator
Work with FragmentsImproved Generation Algorithm
Faster and smarterBetter Screen LayoutsUse Prediction DatabasesBetter tools for faster work-up
31
“What’s New” Documents
See website for complete “What’s New” documentsWill be available shortly
Or I can send them upon request
32
Outline
Secrets of Version 11 Revealed!What’s New in NMR
Automatic Quantitation Using Macros and ChemBasic
Database Searching TipsBe a DB search guru
Macro PossibilitiesMeet “Joe Macro”
Advanced Chemistry Development, Inc. (ACD/Labs)
A Prototype System for Automated Quantitation and Purity Analysis with
NMR
Brent LefebvreNMR Product Manager
NMR Workshop Topic #2
34
What was the problem being solved?
The results of activity screening depends on two things:
ActivityConcentration
Need a test for HT automated quantitation
35
What tools were available to solve it?
ACD/Automation ServerACD/1D NMR Processor, ACD/HNMR Predictor and ACD/ChemSketch
Macro process in the ProcessorChemBasic in ChemSketch
Enough processing tricks here to do it
36
Solution Design
Option #1Assign structure to spectrum# of Protons per peak knownAccurate quantitation possible against all peaks in spectrum
ConsError proneAssignment needs to be perfectSolvents or impurities cause problems
37
Solution Design
Option #2Same as #1, but use only 1 peakLess interference from impurities
ConsInaccurateDependence on a single integration area is too high risk
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Solution Design
Option #3Use Aromatic regionSum # of aromatic protonsMeasure total integral of region
ProsAccurate and more robust than other approachesAccurate assignment not needed
39
Details of the Design
Integration measured against referenceExternal calibration of Eretic peak necessary
Number of aromatic and exchangeable protons counted on proposed structure‘Best’ number of protons per integral foundQuantity determined and reported
40
Quantitation Spectra
M4HBA90
7.5 5.0 2.5 0Chemical Shift (ppm)
41452827
OH
O CH3
Eretic Signal(Quantitation Reference)
41
Integral Value per Proton = ?
In this case two protons contribute to each resonance.
So:
Integral (per proton) = 13.7
How can this be Automated?
M4HBA90
8.0 7.5 7.0 6.5 6.0Chemical Shift (ppm)
2827
OH
O CH3
42
How Many Protons Contribute to Each Integral?
M4HBA90
8.0 7.5 7.0 6.5 6.0Chemical Shift (ppm)
2827
OH
O CH3
Correct Answer (Hopefully)
Possible Answers
Testing Funnel
1
2 5
36 4
78
43
M4HBA90
8.0 7.5 7.0 6.5 6.0Chemical Shift (ppm)
2827
Proton Count per Integral RegionExample #1
1
2 5
36 4
78
O H
O C H 3
Here: estimate 4-5 protons in this region
An acceptable analysis has to:
1. duplicate the 1:1 intensity ratio
2. fit 4-5 proton expectation
Test #1
1. Proton counts have to be in the same ratio as the measured integral values.
2. Sum of protons has to be in a reasonable range
44
Example #1
1
2 5
36 4
78
1 1 sum=2
2 2 sum=4
3 3 sum=6
4 4 sum=8
M4HBA90
8.0 7.5 7.0 6.5 6.0Chemical Shift (ppm)
2827
OH
O CH3
Protons per Integral
Trial Values
Correct Analysis Found
45
Example #2
8.5 8.0 7.5Chemical Shift (ppm)
171360172169
N O
CH3
OH
N
HH
H
Estimated 5-6 protons in this region
A proposed analysis has to:
1. duplicate the 1:1:2:1 intensity ratio
2. fit 5-6 proton expectation
1
2 5
36 4
78
46
Example #2protons per integral – trial values
8.5 8.0 7.5Chemical Shift (ppm)
171360172169
1 1 2 1 sum = 5
2 2 4 2 sum = 10
3 3 6 3 sum = 15
4 4 8 4 sum = 20
N O
CH3
OH
N
HH
H
Protons per Integral -
Trial Values
Correct Analysis Found
47
Automatic Reality Check
8.5 8.0 7.5Chemical Shift (ppm)
171360172169
Compare results with a dependable but less accurate method
– require agreement within a range
– (169+172+360+171)/5.5 = 159 vs. 173
– 173 is close enough to the alternative estimate of 159 to pass
48
How well does it work?
These results need to be validated against
NMR by handExternal gold standard
Tests are ongoingResults will be available soon
49
Other Tests
Remove OutliersAnalyses that passed are screened for consistency - Outliers are removed
Special CasesIdentify and skip special casesReport an error for failed analyses
50
Automation
All of these calculations are done in the ACD/Labs macro language and ChemBasicThis can then be automated with ACD/Automation ServerThe goal being:
Unattended Automated Quantitation
51
What’s Next?
Extend the Quantitation capabilities by building it into the software
If there is enough interest…
Continue to use ChemBasic and Macros to solve similar problems
Any suggestions?
52
Acknowledgements
ACD/LabsRobin MartinArvin Moser
PfizerClaude JonesTom O’ConnellPatrick WheelerShen YangWei WangHong WangTorren Peakman
53
Outline
Secrets of Version 11 Revealed!What’s New in NMR
Automatic Quantitation Using Macros and ChemBasic
Database Searching TipsBe a DB search guru
Macro PossibilitiesMeet “Joe Macro”
Advanced Chemistry Development, Inc. (ACD/Labs)
Database Searching Tips
- Be a DB Search Guru
Brent LefebvreNMR Product Manager
NMR Workshop Topic #3
55
Database Searching Tips
Database SearchingHighlight hit dataUsing lists to do intersecting and subtraction searchesPull hits directly into Specman for comparisonRetrieve all hits automatically before a search
56
Data Hit Highlighting
Data found is highlightedHelps locate relevant hits when scrolling through list
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Using Lists
The List menu in SpecDB is very powerfulAllows you to do all sorts of thing with multiple searches
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List Commands
MergeIntersectSubtractDuplicateSubtract and DuplicateSubtract Current IDAdd Current ID to BSet IDsSwitchUndoLoadSave
61
Aldrich Database Search
Here is what we know:Benzene group is presentCarbonyl is notOnly interested in chloroform spectraNo HalogensCarbon peak at 165 PPMProton peak at 5.5 PPM
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Aldrich Database Search
Substructure SearchBezeneLimits list to only aromatics
List A: 25,743 recordsList B: 35,164 records
63
Aldrich Database Search
Duplicate ListPut result of search step 1 into B list as well.
List A: 25,743 recordsList B: 25,743 records
64
Aldrich Database Search
Substructure SearchCarboxylLimit A list to Carboxyl and benzene containing structures
List A: 1,816 recordsList B: 25,743 records
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Aldrich Database Search
Subtract List A from List BReturns all structures with bezene ring, but not carboxyl group
List A: 23,927 recordsList B: 1,816 records
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Aldrich Database Search
Parameter SearchSearch for records with Chloroform as the solventLimit A list to records in that solvent
List A: 6,109 recordsList B: 1,816 records
67
Aldrich Database Search
Duplicate List A to BJust in case. ☺
List A: 6,109 recordsList B: 6,109 records
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Aldrich Database Search
Formula SearchWe know there are no halogens
Search “F” in formula searchSubtract and Duplicate
Search “Cl” in formula searchSubtract and Duplicate
Search “Br” in formula searchSubtract and Duplicate
List A and B: 3,674 records remain
69
Aldrich Database Search
Carbon peak SearchPeak observed at 165 PPM
Search between 160-170 PPM
List A: 1023 recordsList B: 3674 records
70
Aldrich Database Search
Peak Search1H NMR Peak observed at 5.5 PPMSearch between 5 and 6 to be safe
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Aldrich Database Search
Peak Search1H NMR Peak observed at 5.5 PPMSearch between 5 and 6 to be safe
List A: 158 recordsList B: 6,109 records
75
Pull Hits into Processor
Get search hits directly in Processor windowCompare hit spectrum easily to search spectrum
83
Outline
Secrets of Version 11 Revealed!What’s New in NMR
Automatic Quantitation Using Macros and ChemBasic
Database Searching TipsBe a DB search guru
Macro PossibilitiesMeet “Joe Macro”
Advanced Chemistry Development, Inc. (ACD/Labs)
The Joe MacroWhat is possible with
Macros?
Brent LefebvreNMR Product Manager
NMR Workshop Topic #4
85
Joe Macro
Designed by Arvin Moser Upon special requestUtilizes Chembasic, Chembasic forms, Report Template forms and a Macro
87
How Does it Work?
User chooses to activate macroOr it is activated automatically when a spectrum is imported
User a walked through the process…
95
ChemSketch Report – Page 1
ASCI-1_A1_15_1D1H.esp
18 16 14 12 10 8 6 4 2 0 -2 -4 -6 -8Chemical Shift (ppm)
3.03
2.01
0.96
10.0
1
7.66 7.
667.
63 7.51
7.40
3.87
3.78
3.75
Acquisition Time (sec) 4.5001 Comment T.Spitzer u0002-5-15_d5xf_H1Date Jun 3 2007 Date Stamp Jun 3 2007File Name C:\Work\My Documents\Product Management\ASCI\Test_1
Data\Data_A1_400V_HSQC-DEPT\ASCI-1_A1_15_1D1HFrequency (MHz) 400.10 Nucleus 1HNumber of Transients 16 Original Points Count 49506Points Count 65536 Pulse Sequence s2pulSolvent DMSO-d6 Spectrum Offset (Hz) 2000.4858Sweep Width (Hz) 11001.10 Temperature (degree C) 29.000
1H NMR (400 MHz, DMSO-d6) δ ppm 3.78 (3 H, s), 3.86 (9 H, m), 7.40 (2 H, s), 7.51 (1 H, d, J=7.9 Hz), 7.65 (2 H, m), 10.01 (1 H, s)
22 10 2007Date:11 4 1
6
2
O15
16 5
3
17
O12
18
21
O25
1924
O7
O9
O13
20
O22
CH38
CH314
CH310
CH323
H24a
96
ChemSketch Report – Page 2ASCI-1_A1_15_1D1H.esp
5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)
0
0.25
0.50
0.75
1.00
Nor
mal
ized
Inte
nsity
3.03
9.12
M01(s)
M02(m)
3.87
3.86
3.78
3.78
3.75
ASCI-1_A1_15_1D1H.esp
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0Chemical Shift (ppm)
0
0.25
0.50
0.75
1.00
Nor
mal
ized
Inte
nsity
2.01
0.96
1.93
M03(s)
M04(d)
M05(m)
7.66 7.
667.
65
7.63
7.63 7.
517.
507.
40
97
Possibilities Abound
Macros can do wondrous thingsFrom advanced automatic processingTo wizardsTo manual processes in a specific order
100
Enter Manual Mode
Modes that are available:Integration, BaseLine, Phase, Peak Picking, Annotation, Edit Spectrum, Reference, Assignment, Multiplets, Peak Fitting.
Place this command in the middle of a macro
Macro then pauses and lets a user perform a manual operation
101
Increase your Efficiency
A macro can undoubtedly increase your efficiencyAnalyze what you do to your spectraIf there are common threads, try to macro-ize it!
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