A Computerized System for Storing, Retrieving, and Correlating NMR Data FEATURE ARTICLE Herman Skolnik Hercules Incorporated, Research Center, Wilmington, Delaware •9899 (Received 20 August 1971) A new indexing concept, using the author's notation system, is described for storing, retrieving, and correlating NMR data via computer processing. INDEX HEADINGS:Computerized data system for NMR; Indexing system; Notation system. High resolution nuclear magnetic resonance (NMR) spectroscopy is an important tool in organic chemistry for qualitative and quantitative analyses and in con- firmation of structures, resolution of conformational problems, and study of rate processes. The importance and value of NMR arise from the unique and char- acteristic chemical shifts of protons in organic com- pounds. The resultant NMR chemical shift spectrum, although primarily due to the protons in each proton group, is modified by the presence of other nuclei in the molecule. The connection between the chemical shift value and structure is thus somewhat empirical. A meaningful correlative index of chemical shift values is essential for the effective use of NMR data. The Sadtler Chemical Index 1 and the Varian Func- tional Group Index 2 have been used extensively for relating basic proton and environmental groups with proton chemical shifts. Because these two methods require manual indexing from as many viewpoints as there are proton groups and because neither method includes more than a few atoms of the full structure, a method was introduced recently that eliminated these two disadvantages. 3 The new correlative method was based on a linear notation system 4 in which symbols are used to express various combinations of carbon and hydrogen, such as CH3-, -CH2-, >CH-, -CH=, ~CH, =CH2, and other atoms and hydrogen, such as -NH~, >NH, -OH, and -SH. The notation of each organic com- pound and the chemical shifts of each proton group in the compound constituted the computer input which, in turn, was processed in the computer by a permutation or wraparound program that yielded as Table I. Computer output of notation and chemical shifts for propyl alcohol. Notation and proton group Chemical shift H QCCA ]2~1-3.58-1.57-0.92 HQ C CA 2.28-13.58]-1.57-0.92 HQC C A 2.28-3.58-]1.571-0.92 HQCC A 2.28-3.58-1.57-10.9__2_ ] many index entries as there were proton groups (with their chemical shift data) in each molecule. Thus, for propyl alcohol, CH3CH2CH20H or ACCQH by the notation system, the output contained four proton group retrieval points from the single input as shown in Table I. In addition, a computer program was written to yield an output by increasing value of the chemical shifts of any proton group relative to its neighboring groups. Thus, with one input per compound, the method yields as many outputs as there are proton groups and a printout by increasing chemical shift values. Applying the system to the 700 spectra in Vols. 1 and 2 of the Varian Spectra Catalog disclosed one major disadvantage: The linewidth for output required an allocation of 80 characters for the notation and 120 for the chemical shift data. Thus, even large- size computer paper could not contain the complet e notation and all associated chemical shifts for many Table II. Notation symbols. Single-bonded Carbons Fused or Double-bonded Triple-bonded bridgehead -CHz A >CH~ C >CH- Y >C< X Carbonyl =CH~ E ~-CH U >CH- J =CH- B ~C- V > C < T =C< D =C< R =C= X Other elements and carbonyl Halogen Oxygen Nitrogen Other >C=0 K -CH=O KH O -C-~OH KQH -F F -O- Q -Br G =O Q O -I I CO W -CI L -O-O- Q2 -OH QH > NH M -H H -NH2 MH -S- S >N- N -SH SH ~N Z =S S =N- Z >SO SQ -N=O ZQ >SO2 SW =NOH ZQH P P -NO2 ZW # ® 1 & L Character symbols Cyclic moiety • Atoms between bridgeheads in a cyclic moiety Fused or bridgehead atom other than carbon; placed following notation symbol Ionic form Symbol for condensed ring moieties -1 Polymer repeating unit Used to denote atoms (other than above) with atomic symbol, e.g., &NA for sodium Cis, beta (rosins and steroids), cxo, and axial designation Trans, alpha (rosins and steroids), endo, and equatorial designation Volume 26, Number 2, 1972 APPLIED SPECTROSCOPY 173
Transcript
A Computerized System for Storing, Retrieving, and Correlating NMR Data
FEATURE ARTICLE
Herman Skolnik
Hercules Incorporated, Research Center, Wilmington, Delaware •9899
(Received 20 August 1971)
A new indexing concept, using the author's notation system, is described for storing, retrieving, and correlating NMR data via computer processing. INDEX HEADINGS: Computerized data system for NMR; Indexing system; Notation system.
High resolution nuclear magnetic resonance (NMR) spectroscopy is an impor tant tool in organic chemistry for qualitative and quant i ta t ive analyses and in con- firmation of structures, resolution of conformational problems, and s tudy of rate processes. The importance and value of N M R arise from the unique and char- acteristic chemical shifts of protons in organic com- pounds. The resultant N M R chemical shift spectrum, although primarily due to the protons in each proton group, is modified by the presence of other nuclei in the molecule. The connection between the chemical shift value and structure is thus somewhat empirical.
A meaningful correlative index of chemical shift values is essential for the effective use of N M R data. The Sadtler Chemical Index 1 and the Varian Func- tional Group Index 2 have been used extensively for relating basic proton and environmental groups with proton chemical shifts. Because these two methods require manual indexing from as many viewpoints as there are proton groups and because neither method includes more than a few atoms of the full structure, a method was introduced recently tha t eliminated these two disadvantages. 3
The new correlative method was based on a linear notat ion system 4 in which symbols are used to express various combinations of carbon and hydrogen, such as CH3-, -CH2-, > C H - , -CH=, ~CH, =CH2, and other atoms and hydrogen, such as -NH~, > N H , -OH, and -SH. The notat ion of each organic com- pound and the chemical shifts of each proton group in the compound const i tuted the computer input which, in turn, was processed in the computer by a permutat ion or wraparound program tha t yielded as
Table I. Computer output of notation and chemical shifts for propyl alcohol.
Notation and proton group Chemical shift
H QCCA ]2~1-3.58-1.57-0.92 HQ C CA 2.28-13.58]-1.57-0.92
HQC C A 2.28-3.58-]1.571-0.92 HQCC A 2.28-3.58-1.57-10.9__2_ ]
many index entries as there were proton groups (with their chemical shift data) in each molecule. Thus, for propyl alcohol, CH3CH2CH20H or ACCQH by the notat ion system, the output contained four proton group retrieval points from the single input as shown in Table I.
In addition, a computer program was writ ten to yield an output by increasing value of the chemical shifts of any proton group relative to its neighboring groups. Thus, with one input per compound, the method yields as many outputs as there are proton groups and a pr intout by increasing chemical shift values. Applying the system to the 700 spectra in Vols. 1 and 2 of the Varian Spectra Catalog disclosed one major disadvantage: The linewidth for output required an allocation of 80 characters for the notat ion and 120 for the chemical shift data. Thus, even large- size computer paper could not contain the complet e notat ion and all associated chemical shifts for many
Table II. Notation symbols.
Single-bonded
Carbons Fused or
Double-bonded Triple-bonded bridgehead
-CHz A >CH~ C > C H - Y > C < X
Carbonyl
=CH~ E ~-CH U > C H - J =CH- B ~C- V > C < T =C< D =C< R =C= X
Other elements and carbonyl
Halogen Oxygen Nitrogen Other
>C=0 K -CH=O KH
O
-C-~OH KQH
- F F - O - Q - B r G =O Q
O
- I I CO W
-CI L - O - O - Q2 - O H QH
> NH M - H H -NH2 MH - S - S
> N - N - S H S H
~N Z =S S =N- Z >SO SQ -N=O ZQ >SO2 SW =NOH ZQH P P -NO2 ZW
# ® 1 &
L
Character symbols Cyclic moiety
• Atoms between bridgeheads in a cyclic moiety Fused or bridgehead atom other than carbon; placed following notation symbol Ionic form Symbol for condensed ring moieties
-1 Polymer repeating unit Used to denote atoms (other than above) with atomic symbol, e.g., &NA for sodium Cis, beta (rosins and steroids), cxo, and axial designation Trans, alpha (rosins and steroids), endo, and equatorial designation
Volume 26, Number 2, 1972 APPLIED SPECTROSCOPY 173
277 CH3COCHCH2COOCH2CH3 AKY (KQCA)CKQCA I COOCH2CIIa
215 CH3COOCH2 AKQC, 2
CH3CO0~H~
compounds in the Varian Spectra Catalog, and we had to resort to a double line per compound or to limit the chemical shift da ta to the indexed pro ton group in the output . But even allowing 80 spaces for the notat ion does not make for a line as readable as we would like. For tuna te ly , work on using the notat ion sys tem for producing a nota t ion symbol index 5 and a chemical f ragment nota t ion index G led to a great ly improved sys tem for N M R d a t a - - t h e subject of this paper.
I. T H E N O T A T I O N SYSTEM
The nota t ion sys tem employs a set of nota t ion symbols, listed in Table I I , t ha t designates the bonding and number of hydrogens associated with carbon in par t icular and with other a toms in general. Allocating 12 nota t ion symbols (single let ters of the alphabet) to carbon (denoting bonding, number of a t t ached hydrogen, and fused or br idgehead a tom) is in ha rmony with the predominance of carbon and hydrogen a toms in organic chemistry. Because of the high occurrence of the carbonyl group, it is assigned a separate nota t ion symbol, viz., K.
Chemical s t ructures are represented with the notat ion sys tem in an a t o m - b y - a t o m correspondence with the s t ructural formula as usually drawn, i.e., for acyclic compounds f rom left to right with functional groups at the r ight-end position, or for cyclic struc- tures f rom the a tom having the highest position number to the a tom in position 1. Thus, the notat ion sys tem is in accord with accepted number ing schemes as well as with the convent ion of drawing s t ructural formulas. This is i l lustrated in Table I I I for acyclic compounds and in Table IV for cyclic compounds.
Cis and trans isomers are differentiated by the characters I for cis a n d - for trans, as i l lustrated in the
Table IV. Notations for cyclic compounds.
Yariaa No. Structure Notation
3 2
32 CH2-CHCH3 . CY(A) Q. \ /
O
3 2 33 CH2-CH~ . C3Q.
4
NH
94 ~ ~ C H O . B3D (KI-I)S.
S
157 CHa . B5D (A).
4
161 CH~OH . B5D (CQH). [
4
124 OH . B4D (QH) D (QH).
4
550 0 . B4R2(~KB2K. 8 II
6 3
O
552 O . B4R2(~KD (A)BQ.
e ~ / ~ - C H 3
487 . i ~ . 32 . B2JB2J: C.
a
272 CH3 . X (A2)JCBD (A)J: C. 21
CH3 ~.~'~
CH3 s
174 Volume 26, Number 2, 1972
Table V. Relating proton groups via structural formula.
Varian Structural formula No. and chemical shifts
1 CH3---OH 3.47 1.43
14 CHa-CH2--OH 1.2 2.5 3.7O
43 CH3-CH2-CH2-OH 0.92 1.57 3.58 2.28
44 (CH3) ~-CH-OH 1.20 4.00 1.60
following notations for cis- and trans-crotonic acids:
C H - C H 3 C H - C H a
II II CH-COOH HOOC-CH
cis- trans-
AB2KQH ( [ ) AB2KQH (_)
These characters thus allow us to differentiate between the methyl chemical shift (2.03) in cis-crotonic acid and (1.90) in trans-crotonic acid.
II. RELATING PROTON GROUPS VIA STRUCTURAL FORMULA
The most meaningful method for relating each proton group in a molecule with its chemical shift is via the structural formula as illustrated in Table V. Writing the structural formula with sufficient space between the proton fragments for assigning the chemical shift under each proton fragment yields a highly readable format. This format can be converted into an index format by using a virgule (or slash) to separate the proton fragments and a double virgule
Table VI. Proton group/chemical shift index for a series of alcohols in increasing chemical shift order of the methyl group.
Varian No. Formula and notation Index
575 CHa(CH2)~CH(OH)CH2NH2 A /C /C6/Y(/QII) /C / M H / / AC7Y(QH)CMtI 0.89/1.28/ /3.50/1.75 /2.51/1.75//
282 CH,(CHgsCtI~OH A /C /C7/C / Q H / / AC9QH 0.91/1.28/ /3.63/2.03//
43 CH3CH2CH20It A /C /C /QH// AC2QH 0.92/1.57/3.58/2.28//
The wraparound program and computer alphabet- ization of the output results in a proton group/ chemical shift index by as many ways as there are proton groups in each molecule from a single input [such as (23)]. This is in contrast to the Sadtler and Varian indexes, which require manual indexing from as many viewpoints as there are proton groups. Furthermore, neither of the two systems shows the full molecule in the index.
It is quite apparent that a computerized system using the above structural formula fragment concept,
Table IX. Proton group/chemical shift index for the moiety CH3COCH= or AKB.
regardless of how inviting it is, would be awkward and space-consuming for more complex structures. Structural formula fragments are particularly difficult to delineate for cyclic structures without invoking arbitrary rules.
These difficulties, however, disappear when the notation system is used to delineate the fragments in a molecular structure.
III. RELATING PROTON GROUPS VIA THE NOTATION SYSTEM
Because the notation system corresponds essentially atom by atom with the way structural formulas are drawn, uses the same numbering rules as generally accepted, and is based on combinations of carbon and hydrogen, it is particularly suitable for relating proton groups with chemical shifts. Moreover, the notation
system is completely compatible with computer processing operations.
Input by the notation system for propyl alcohol and computer processing of the fragments yield the following :
h /C /C /QH / / (Input) (3a) 0.92/1.57/3.58/2.28// ,
C /C /QH / / i / (3b) 1.57/3.58/2.28//0.92/,
C /QH / / A /C / (3c) 3.58/2.28//0.92/1.57/,
QH / / A /C /C / (3d) 2.28//0.92/1.57/3.58/.
It is quite apparent that (1), (2a), and (3a) are equivalent as are their products from computer
APPLIED SPECTROSCOPY 177
Table XI. Proton group/chemical shift index for the moiety CH.~COO- or AKQ.
processing Ecompare (2b), (2c), and (2d) with (3b), (3c), and (3d)~. The advantage of the notation system over the structural formula fragments Ee.g., (3a) over (2a) or (1)1 is the use of single letters to denote com- binations of carbon and hydrogen and the bonding associated with the carbon. This advantage is par- ticularly pertinent with highly substituted or complex acyclic compounds and in cyclic structures. For example, the proton group/chemical shift index for 3-diethylamino-2,2-dimethylpropionaldehyde (Varian No. 548) by the notation system is as follows:
0.97 I
(CH3CH2)2NCH2C(CH~)2CHO I I I I 2.50 2.55 1 .07 9.57
~AC, 2NCX(A2)KH, (4)
A /C,2N /CX( /A2) / K H / / (Input) (4') 0.97/2.50 /2.55 /1.07/9.57 / / .
In (4'), A /C,2N / is equivalent to (AC)2N and to (CH3CH2)2N; C X ( / A 2 ) / is equivalent to CH2C(CH3)~; and KH is equivalent to CHO. Thus, even with the high compression of information, (4') discloses every proton group as an index point and, at the same time, every fragment in the molecule and the full molecule. The proton group/chemical shift index for 1,4-naphthoquinone (Varian No. 550) by the notation system is as follows:
8.07 0 B K 7.77 I ~ 6.97 / / ~ /
~ , ~ / ~ / B R B *1 I I
B R B / \ \ / \ /
7.77 I % 6.97 B K 8.07 0 ~ .B4R2@KB2K. -~.BB2BR2@KB2K. (5)
Cyclic structures in the notation system are char- acterized by left and right terminal periods, as illustrated in (5'). Both (4') and (5') contain a maxi-
mum amount of information within a minimum space allocation. Each has as many fragments as there are proton groups with chemical shifts, and each frag- ment is associated with its neighboring groups within the full molecule, and this remains true for each of the wraparound products.
Table VI illustrates the proton group/chemical shift index by the notation system for a series of alcohols in increasing chemical shift order of the methyl group protons. Table VI illustrates rather pointedly the correlative power of the indexing con- cept. Thus, the methyl group protons in Varian compound numbers 575, 282, and 43 are very much alike and similarly modified by being removed from the hydroxyl group by three or more methylene groups ; the methyl group protons in Varian compound numbers 45 and 87 show the same chemical shift effect of similar glycol neighboring groups ; the methyl group protons in Varian compound numbers 44, 14, and 86 show the same chemical shift effect of -CHOH- and -CH2OH. In methyl alcohol, in which the methyl group protons are adjacent to the hydroxyl, the chemical shift is unlike that of the other alcohols in this series but somewhat similar to the protons in the methoxy fragment of Varian compound number 120, i.e., the NMR spectrum of methyl alcohol categorizes it as containing a methoxy group (see Table XII) and a hydrogen proton, i.e., as AQ /H / / i n the notation fragment index.
IV. EFFECT OF VARIOUS ENVIRONMENTS ON THE METHYL GROUP
In view of the correlative power of the indexing concept exhibited in Table VI, it was further evalu- ated with other environments that affect the methyl group. The compounds and their chemical shift data were selected from Vols. 1 and 2 of the Varian Spectra Catalog.
Relative to the hydroxyl function (Table VI), the carbonyl function exhibits a slightly greater effect on the methyl group protons (Table VII). Thus, the methyl group shift values in the fragment CH3CH2CO- (or ACK-) range from 1.05 (in burn- none) to 1.30 (in acetamidomethylidene bispropio-
APPLIED SPECTROSCOPY 179
Table XII. Proton group/chemical shift index for the moiety CHsO- or AQ.
nate). Within this range, Table VII reveals the in- creasing effect on the methyl chemical shift of the amide group, aromaticity, and the carboxyl group, relative to that in butanone.
The effect of the carbonyl group when adjacent to the methyl group is shown in Table VIII for a series of CH3COCH2- (AKC) and CH3COCH<(AKY) compounds, in which the chemical shift of methyl group protons ranges from 2.12 to 2.35. The electronic effects of neighboring groups beyond the carbonyl are quite revealing in Tables VIII-XI.
As revealed in Table XII, oxy and carboxy have a marked effect on the protons in the attached methyl group. Chemical shifts of the methoxy group attached to alicyclic saturated carbons range from 3.33 to 3.47. Methoxy groups attached to unsaturated and cyclic carbons have chemical shifts within the carbomethoxy range, viz., 3.67-3.96, with the methoxy groups falling between 3.75 and 3.90.
V. ALPHABETIZATION OF PERMUTED INDEXES
Whereas the proton group notation fragment index input is easily alphabetized to place together molecules
of similar nuclei, the wraparound indexes cannot be alphabetized meaningfully from a left-to-right com- puter alphabetization. Consequently, the computer program needs to be such that the first term in each index is examined for the right-hand parenthesis and for the double virgule. If either or both are present, the first term is then alphabetized with the final term rather than the second term; if with a double virgule subsequent alphabetization is from right to left; if with a right-hand parenthesis and a single virgule the next alphabetization is with the second term and the next to last term.
Thus, in the case of 3-methoxybutanol (Varian No. 120) in Table XII, alphabetization would place it with
A /
AQY \
C
In the case of carbmethoxycyclopropane (Varian No. 112) in Table XII, alphabetization would place it with
AQKYC2.
APPLIED SPECTROSCOPY 181
Table XIII. Alphabetical proton group/chemical shift index for the Varian No. moiety CHsO- or AQ.
Table XII I illustrates the alphabetical order for the compounds in Table XII.
Alphabetization program logic is more clearly illus- trated with arrows in the following examples from Table XII :
100
Notation fragment alphabctization
A Q / / U V / B / n /
69 A Q / C / C V Z / /
258 [ I
AQ) / S /BD ( /B /B /A) . / / . B / ( /
172 AQ)D(/iV[H). / / . B 4 D
The program needs to be such that in compounds 258 and 172 the second and next to last terms, which are nuclei neighbors of the last term, are examined and placed in alphabetical order.
The alphabetical order in Table XI I I successfully brings together structurally similar compounds, such as compounds 69 and 28; compounds 258, 266, 162, and 249; compounds 106 and 57; compounds 113 and 576; and compounds 112, 284, 446, 120, 446, and 419. Within structurally similar compounds, the alpha- betical arrangement reveals the effect of different nuclei beyond the structural similarity, such as for AQKY-.
VI. CONCLUSIONS
Magnetic variations of the same proton group arises from subtle, and sometimes obvious, differences in shielding. The extent of the differences depend on the magnetic anisotropy of many or all of the other groups in the molecules and their orientations with respect to other nuclei.
The indexing concept presented in this paper pro- vides a new method for relating groups with neigh- boring groups and with every group in each molecule ; for correlating the same proton group with the various environmental groups it is associated with in different molecules; and for computer processing of a single input per molecule to yield a proton group/chemical shift index under as many retrieval points as there are proton groups in each molecule, alphabetically by the proton groups or numerically by the chemical shift data.
1. "Chemical Shift Index Chart," Sadtler Research Laboratories , Inc., Philadelphia, Pa., 1967.
2. N M R Spectra Catalog (Varian, Palo Alto, Calif, 1962 and 1963), Vols. 1 and 2.
3. H. Sholnik, J. Chem. Doc. 10, 216 (1970). 4. H. Skolnik, J. Heterocyclic Chem. 6, 689 (1969). 5. I I . Skolnik, J. Chem. Doc. 11, 120 (1971). 6. H. Skolnik, "A Chemical F r a g m e n t Nota t ion Index , " J.
