Chemical shifts of protons in nitrogen-containing organic compounds

Chemical Shifts of Protons in Nitrogen-Containing Organic Compounds George Slomp and James G. Lindberg’ Research Laboratories, The Upjokn Co., Kalamazoo, Mich.

Downloaded by UNIV OF SUSSEX on September 13, 2015 | http://pubs.acs.org Publication Date: January 1, 1967 | doi: 10.1021/ac60245a003

Currently available proton chemical-shift data for NMR spectroscopy are mostly concerned with tabulations for compounds containing carbon, hydrogen, and oxygen. Because of the importance and large number of organic compounds containing nitrogen, structural and chemical-shift data on 2306 hydrogens influenced by nitrogen in a variety of ways have been correlated and charted. The intramolecular shielding effects of the nitrogen are discussed, and general trends are noted which aid in the use of NMR as a tool for structural determination.

PRESENTLY AVAILABLE TABULATIONS of proton chemicalshift data are concerned mostly with C, H, and 0 compounds (1-3). More information is needed on the resonance frequency of protons in nitrogen-containing organic compounds. This need is acute because a large variety of these protons may be encountered in nmr spectroscopy. Therefore, proton magnetic resonance spectra were obtained on many organic compounds which contain nitrogen atoms, and the intramolecular shielding effects of the nitrogen atoms on the resonance frequency of nearby protons were investigated. With a nitrogen atom present in the molecule, structural variations include the number and type of nitrogen functions present, their location relative to the proton in question, the substituents on the nitrogens, and the charge state of the nitrogen. Since these all affect the chemical shift of nearby hydrogen atoms, they had t o be oonsidered in this correlation of structure and resonance frequency. ORGANIZATION OF THE DATA

The structural environments about the various hydrogen atoms studied were coded by the method employed by Varian in their well known spectra catalogs ( I ) , so that the effects of the various features could be compared readily. Three additional hydrogen types were added t o the list of 21 main groups used by Varian: the a- and @-hydrogens of indole, designated 22a and 22@, and the N-hydrogen of an imine, designated 23 (Figure 1). In the use of the Varian code, an ambiguity was encountered with the Llm designation. The adjacent group designated byL has one doubly bonded and one singly bonded substituent; the substituents designated by 1 and m both have one double bond and one single bond available for attachment. Thus, owing to the alphabetical requirement, it cannot be determined from the code word which substituent is attached to the adjacent group by the double bond and which by the single Present address, Baylor University, Waco, Texas. (1) N. F. Chamberlain, ANAL.CHEM., 31, 56 (1959). A new edition of the charts is available from Dr. Chamberlain. (2) N. S. Bhacca, D. P. Hollis, L. E. Johnson, E. A. Pier, and J. N. Shoolery, “NMR Spectra Catalog,” Varian Associates, Vols. I and 11, 1962 and 1963. (3) K. Nukoda, 0. Yamamoto, T. Suzuki, M. Takechi, and M. Ohnishi, ANAL.CHEM.,35, 1892 (1963).

60

ANALYTICAL CHEMISTRY

22a

=

H

Figure 1. Additional hydrogen types not coded by Varian bond. The code word 1-Llm, for example, may mean either an imine-substituted olefin (I) or a vinyl-substituted imine (11). In reality, hydrogens of both types showed the same chemical shift and therefore this ambiguity was ignored. I

C-

// \

CH 3-C

N=

I

N-

\

c==

I1

The Varian code describes a hydrogen in terms of the main group it is part of, expressed as a n arabic number; in terms of the adjacent groups, expressed as capital letters; and in terms of the substituents on the adjacent groups, expressed as lower case letters. From the code we can distinguish three types of interaction between the nitrogen in the organic compound and the proton in question. In primary interactions, the nitrogen is a part of the main group and appears in the arabic number part of the code. In secondary interactions, the nitrogen is a part of the adjacent group and appears in the capital letter designations of the code. In tertiary interactions, the nitrogen is a part of a substituent on an adjacent group and appears in the lower case letters of the code. Nitrogens further removed from the proton in question would not appear in the Varian code and were not included in this survey. A list of main groups which contain nitrogen is shown in Table I, where H is the proton in question and A stands for a n adjacent group. Adjacent groups which involve nitrogen are shown in Table 11; T symbolizes any type of main group. The nitro group was not included in this tabulation. No examples of nitro compounds were encountered. Substituent groups containing nitrogen are shown in Table 111, where T is used t o symbolize the main group and A stands for some adjacent group. Although the substituent I dces not contain a nitrogen it was included because it may have a nitrogen (or carbon) attached at the double bond. Since this information does not appear in the code, it is necessary to refer to the structure for this information. In tertiary interactions the structure of the adjacent group is, of course, limited t o those where A is nonterminating (see Table 111).

/ bears at least one -N=,

Table I. Involvement of Nitrogen in Coded Main Groups (H is the proton of interest and A stands for an adjacent group) 4 15 a. 15 B 15 I A, H

20

22 u

A A”h - H

23

I


A,

Table 11. Involvement of Nitrogen in Coded Adjacent Groups (T is any type of main group) Lm MI Mm N U

T -N-

T-N=C

/

/’

T-N=N-

T-N

/

T-C-N

\

\‘

To evaluate the effecls of the various nitrogen-to-proton interactions, proton che nical-shift data were collected from our files and organized in a systematic way. A numerical alphabetical arrangement according to the structure code was chosen for ease of retrieval. A tremendous variety of hydrogen types was encountered, all under the influence of nitrogen. The list began with hydrogens of type 1-B Followed by an m, n, or u (methyl hydrogens alpha to meihylene and beta to -N=,

-N

EXPLANATION OF TABLE IV

/

1. Code. The effect of alkyl substituents ( A , B, C, or D ) was about the same and these possibilities have, therefore, been combined in the charts. Thus, the meaning of the term “ A , B, C, or D” is that one and only one of these groups is attached to the main group. When no lower case letters appear in the code, it is understood that only hydrogen or saturated carbon substituents such as a, b, c, or d are attached. Deshielding substituents including nitrogen, oxygen, sulfur, halogens, or multiple bonds, when present, are shown in the code. The effect of unsaturated substituents j , k , I, m, or L; was about the

\

or -C=N). Next, in alphabetical order, came type 1-C plus two lower case letters, one of which was an m, n, or u (methyl hydrogens alpha to methine and beta to -N=, -N

/

or -C=N

and lone other group).

group). The

1-J(methy1 hydrogens adjacent to a carbonyl) and I-K (methyl hydrogens adjacent to a carboxyl) types of hydrogens had but one substituent which was m, n, or u. Next came a group of hydrogens which had secondary nitrogen interactions. These included 1-Lm, 1441, and any one other substituent; 1-Mm, and 1-N followed by any two substituents (see Table I1 for identification of these methyl hydrogen types). Next followed a group of hydrogen types which had tertiary nitrogen interactions. This group included 1-Ow, 1-On, and 1-Ou followed by 1-Qm, l-Qn, 1-Qu (see Table I11 for identification of these methyl hydrogen types). Upon completion of the type 1 main groups, the whole series was continued with hydrogens of types such as type 2 (methylenes), type 3 (methines), and type 4-9 (vinyl hydrogens). In hydrogens of the type 4, the first primary interactions with nitrogen were encountered. Other primary interactions did not occur until hydrogen types 15, 20, 22, and 23. With these hydrogen types having primary nitrogen interactions, all of the possible adjacent groups and substituents were included. Examination of the data showed that hydrogens with many different kinds of adjacent groups and substituents showed similar chemical shift and, where possible, these data were combined to yield, in all, 103 kinds of hydrogens. The results are presented in Table IV. The table is limited to primary, secondary, and tertiary interactions of nitrogen functions. Long range effects are not included nor are interactions with nonnitrogen functional groups except for a few examples of olefins. The table makes only a few distinctions between aliphatic and cyclic main groups. Aromatic main groups are noted. In the analysis of resonance hybrids, only the form with the largest contribution was considered.

:=,=N-H

\

or -N

\

a; 22 B

-N

With type 1-D,

\

three lower case letters fclllowed, one of which was m,n, or u (methyl hydrogens alpha to a tetrasubstituted carbon which

Table 111. Involvement of Nitrogen in Coded Substituents (T is any type of main group and A is an adjacent group) 1

n

m

T-A

\

*N-

T-A-N=

/ B

-CHr

0

-0-

T-A-N

U

/

X

T-A-C-N

T-A-ArN

\ Where A is nonterminating C

-CH-

I

Q -0-co-

D I

-C-

I S

-S-

K

J

-c==o I T

-c=c-

--c==o

I

0 I

V aryl

VOL. 39, NO. 1, JANUARY 1967

61


SM W N

-


o m W

m

*

-v)v)

N

-

.... -I

I

T 11

\ t

0 0

,

0

c)

::

7 2.

m 0 I V X

IT

VJ

I m


--UI

\

-$z I

V

nm

N

\

wo

N-

6)

0

-

v

nN

\

-; -Y-" z1 1

3

N

I

,

r-

\

m

\

'401. 39, NO. 1, JANUARY 1967

-

I

--H

,v=v \\

N

= ,

zI I

5 (u

-VI

P.

N

63

me Loo

(0

mm

m

0'9

PI-

I1

I r-

ow

0

mmi

0'

mo riri

0

4

E9

I I Loo o w


--

r-

1 1

I

r-

L o o

w

om O'P'

ri

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I

w r-

wr-

m

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m

NO

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z z L

L

0

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zI

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0

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r

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W

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b

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z.-

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0

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0

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0

m. 4 I 0

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4 0 0

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m. 4

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t

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0

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J

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> 0'

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0

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z I1 xu

> 0'

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0

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=.

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7

7

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2: w2 --rd

Y)

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?mr:

f-p

+As

W

-

i

I Downloaded by UNIV OF SUSSEX on September 13, 2015 | http://pubs.acs.org Publication Date: January 1, 1967 | doi: 10.1021/ac60245a003

-1-

In

(0

2

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+

7 c

.-

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z

3 I

Z

J

r-

r-'

r-

c

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z

P

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VOL. 39, NO. 1 , JANUARY 1967

67

N

m

N

-

-

Lo

N

IC

N

I

u-

I

I

I

2 \

u

I

I1

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u I, V

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E -u- I

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7 3 7

V

-" * - 2 u

-Y

\

I

2 - - 2u

VI

I0\

1

I

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0

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u

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z

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0 I1

I1

I

0

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I \

O

.

IV\

u=o r u=o uV11 I1

I

\ zI I \ o=u,,z-

: : ij

rI \ yo 0

0 0

0

0.

m. a 0 L

0

'-

.-._ z+

68

+

..

zI m

> 1 m

W

5

* *

>

N

0

":?


-

m

0. 0 b

0

b

m.

-. m

-m.

4

m

m

0)


8

E 7 I

>

+

0

z 0 L

0

b

0

=!

o

.

:

-m.

u

4

.-

z

z

7

7

m 4

7 I

0)

.-+ I

m

.-+ I

m

L

0

0. m. 4

.-+ z

>

+ 0

z

. m .-+

>

+

..

2

-+

z

3 I

-J

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m

0)

m

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..

7 c

m


same, and these possitrilities have therefore been combined wherever possible, Thus, the meaning of the term “j, k , I, rn, or G” is that one and ortly one of these groups is present unless otherwise specified. In some cases the inclusion of electronegative substituents, 0.p , q, and s, made no difference in the absorption frequency and these were therefore included in the code designation. 2. Structure. A dangling single bond signifies that a hydrogen or saturated carbon atom is attached. A dangling double bond signifies that a carbon or nitrogen atom is attached by a double bond. The symbol 8 signifies that an unsaturated carbon or unsaturated nitrogen atom is attached in the manner shown. 3. Chemical Shift. Solid lines represent values for the structures shown. Values for protonated derivatives are shown as dotted lines. Values differing by 0.013 ppm (8 Hz) or less are connected t3 show the highly populated regions. Stray values may arise from special long range effects. 4. Range. The range of the highly populated region is reported. Where this ‘was not known, the individual results are recorded, using conimas where applicable. 5. No. This column indicates the number of examples of this type of hydrogen that were encountered. CONCLUSIONS

To a first approximation, the effect of the nitrogen in various structural environments is consistent and additive. Thus, for multiple nitrogen interactions not found in the table a prediction of a particular proton chemical shift can be made by summing the individual contributions of each nitrogen interaction. From the data, it can also be concluded that the deshielding effect of a nitrogen substituent is attenuated by intervening atoms. The effect reaches a hydrogen three single bonds away, or farther if double bonds are involved. Thus, tertiary involvement of the nitrogen brings about a deshielding at the hydrogen of about 0.1 to 0.5 6 when no double bonds intervene. This information can be obtained by comparing the chemical shift of the hydrogen type in question with that of the analogous compound containing no nitrogen. With an intervening cross conjugated double bond, as, for example, in the hydrogens of type 1 4 / n , the deshielding effect of the nitrogen atom three single bonds removed is about 0.6 6 when compared with the nonnitrogen-containing analog. This large deshielding must be attributed to the effect of conjugation of the double bond with the unshared electrons on the nitrogen cy to the double bond. The deshielding effect on a proton by a nitrogen which is two single bonds removed (secondary interaction) was about 0.8 to 1.3 6. The inclusion of the nitrogen in the main group (primary interaction) causes deshieldings which are much larger (see, for example, type 4-A, B, C, or D; A , B, C, or D where the deshielding effect was 2.0 6). A nitrogen atom attenuates the deshielding of nearby unsaturated groups less, than a carbon atom does. This is especially true if the nitrogen atom is conjugated with the

double bond. For example, the addition of a double bond system a to the nitrogen (see I-N j , k , I, m, or u ) causes a 0.7 6 deshielding at the hydrogen three bonds removed. The addition of a second unsaturated system a to the nitrogen causes an additional 0.5 6 deshielding. This is about twice the magnitude of the deshielding expected in the analogous compound having the nitrogen replaced by a carbon. Displacement of the resonance frequency due to protonation of the nitrogen depends on charge localization and on proximity of the proton in question to the nitrogen. Either charge delocalization or intervening carbon atoms attenuate the effect. The effect of protonating a nitrogen in a tertiary involvement is about 0.4 6 deshielding in hydrogens of the type 1-B,C, or D n. Compared to this, the deshielding effect of the nitrogen in 1-L .j, k , I, m, or u is approximately zero. The effect of the protonation of the nitrogen in a secondary interaction is about 0.7 6 deshielding as seen in several examples. It is interesting to note that the methyl hydrogens of acid amides are deshielded about 0.2 6 by the nitrogen substituent. On the other hand, methylene hydrogens under the same circumstances are shielded approximately 0.4 6 by the nitrogen substituent (see 2-A, B, C, or D ; J, n). A methine hydrogen under the same circumstances is apparently not affected by the nitrogen substituent (see 3-A, B, C, or D ; A , B, C,or D; J , n ) . The above phenomena can be exploited by the addition of hydrogen chloride vapors to the nmr sample. This is conveniently done with a medicine dropper. The information obtained from the spectrum of the acidified sample is an aid to structure studies. The resulting displacement in resonance frequencies should correlate with those expected from the proposed structure.

+

+

+

EXPERIMENTAL

Spectra were measured with a Varian A-60 nmr spectrometer calibrated with TMS as zero and chloroform as 7.27 6, using deuteriochloroform for nonpolar substances and deuterium oxide, d6-acetone, d6-dimethylsulfoxide, or d,-dimethylformamide (in order of decreasing preference) for polar substances not soluble in chloroform. Chemical shifts were measured in parts per million downfield from internal TMS except for deuterium oxide solutions in which SDSS was used. In situations where multiplets could not be factored easily, the center of gravity was taken as the chemical shift. ACKNOWLEDGMENT

The assistance of Forrest A. MacKellar and John F. Zieserl in the measurement and interpretation of many of the spectra is gratefully acknowledged. Dr. Bernard Johnson assisted in the tabulation of some of the data.

RECEIVED for review July 15, 1966. Accepted October 19, 1966.


69

Chemical shifts of protons in nitrogen-containing organic compounds

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