and %methyl- 1-indanone (V) were analyzed by LAOCOON I11 (11). The parameters that gave the best fit are given in Table IV. ACKNOWLEDGMENT
The authors thank Sidney Siggia for his discussions and contributions during the course of this investigation and H. A. Bruson of Olin Chemical Corp., New Haven, Conn., for his novel synthesis of the 1-indanones which made this study
possible. The many discussions in every phase of this study with A. I. Cohen of Squibb Institute, New Brunswick, N. J., were extremely helpful and appreciated. The authors also thank Paul A. Strauss of Perkin-Elmer Corp., Norwalk, Conn., for the R-20 spectra and for making the computer facilities at Perkin-Elmer available to the authors. RECEIVED for review February 24,1967. Accepted August 10, 1967.
Structure Determination of Substituted elnzenes by Proton esonance. An Empirical reatment of Substituent Their Utility in Predicting Chemical Shifts John J. R. Reed Esso Research and Engineering Co., Baytown Chemicals Research Laboratory, Baytown, Texas An empirical procedure for predicting the chemical shift of ring protons in any substituted benzene is introduced. The set of all possible substituted benzenes is divided into 12 distinct types of subsets, and the prediction procedure tested In a selected group of these subsets. Of 543 possible unique chemical shifts in a given set, 171 have been observed and predicted to within 0.02 ppm. I t is claimed that all of the 372 remaining shifts can be predicted to good accuracy with the use of 5 1 empirical constants.
IT IS EXTREMELY ADVANTAGEOUS in the determination of molecular structure by NMR to be able to predict the chemical shifts of the protons in a proposed molecule. If the chemical shifts can be predicted with sufficient accuracy, the application of the approximate, first-order spin-spin multiplicity rules will quickly determine whether a proposed molecule can give rise to the observed spectrum. In this paper we present a scheme for rapidly predicting the ring proton chemical shifts of certain substituted benzenes. The scheme involves the use of a set of empirically determined parameters, the application of which is readily recognized from the structural formula of the proposed molecule. Results of this study indicate that, with very few exceptions, ring proton chemical shifts can be predicted to within 0.02 ppm of the observed chemical shifts determined by the firstorder approximation. Experience shows that this is generally adequate to distinguish protons in the aromatic region of 100-MHz spectra. There have been many attempts (1-12) to demonstrate additivity in the effect of substituents on ring proton chemical shifts of substituted benzenes. Even after solvent and concentration effects had been eliminated, disagreements with the additivity principle of Diehl (1) persisted. These so-called anomalies had led to the generally accepted conclusion that substituents affect ring proton chemical shifts through mechanisms other than electron charge density displacement. The many alternate mechanisms which have been proposed include magnetic anisotropy effects, electric field effects, steric interactions, and van der Waals forces. It shall be our contention that, in substituted benzenes, the substituents affect the ring protons in just three distinct ways. 1584
a
ANALYTICAL CHEMISTRY
One of these is an indirect effect, in which the substituent interacts with the ring, which in turn interacts with the proton. This effect is postulated as long-ranged as well as short-ranged. In the direct effect, the substituent interacts through space directly with the proton. This effect is postulated as shortranged only, and its influence is restricted to ortho protons. In the sandwich effect, a proton sandwiched between two substituents receives an additional effect from the substituent pair. This effect is short-ranged only and its influence is restricted to a proton which is ortho to both substituents. N o physical mechanism for these effects is necessary to apply the prediction scheme presented in this paper. However, a quite reasonable physical interpretation can be given for each parameter, and these are presented later. The indirect effects of substituents are subject to perturbations by other substituents on the same ring. We can divide these perturbations into indirect and direct perturbations. These are described more fully under the section on definitions, Because of the difficulty in the application and determination of these perturbation factors, we have tried to avoid them in this paper by restricting the present study to molecules in which these perturbations are small. As will be seen below, we have not been entirely successful, because the agreement between predicted and observed chemical shifts is much poorer in certain molecules, The postulation of a single perturbation factor, however, gives agreement between observed and predicted data within 0.02 pprn for all the data.
(1) P. Diehl, Helr;. Chim. Acta, 49, 829 (1961). (2) A. H. Gawer and B. P. Dailey, J . Chem. Phys., 42,2658 (1965). (3) W. A. Gibbons andV. M. S. Gil, Mol. Phys., 8, 168 (1964). (4) W. A. Gibbons and V. M. S. Gil, Zbid.,9,163 (1965). (5) V. M. S. Gil and W. A. Gibbons, Ibid.,8, 199 (1964). (6) F. Hruska, H. M. Hutton, and T. Schaeffer, Can. J . Chem., 43, 2392 (1965). (7) 3. S. Martin, J . Chem. Phys., 39,1728 (1963). (8) J. S. Martin and B. P. Dailey, Ibid.,39, 1722 (1963). (9) G. W. Smith, J . Mol. Spectry., 12, 146 (1964). (10) H. Spiesecke and W. G. Schneider, J. Chem. Phys., 35, 731 (1961). (11) T. K. Wu and B. P. Dailey, Ibid.,41,2796 (1964). (12) Ibid.,p. 3307.
+lo
NO. OF COMPOUNDS IN EACH SUBSET
c p s 4
r
11
Ri
Figure 1. 100-MEIz spectrum of 1,2,3-trichlorobenzene in CCL (sweep width = 100 Hz) EXPERIhlENTAL
'
All compounds in this study were purchased from commercial sources and were used without further purification. The NMR spectra were obtained on a Varian Model HA100 spectrometer using field sweep with the control signal locked on internal TMS. The concentrations were all 4.0% by weight in CCl, where solubility permitted, and saturated solutions in CCl, in all other cases. Chemical shifts were measured in cps downfield from TMS using a Hewlett-Packard Model 522B electronic counter. These values were converted to the so-called 6scale by dividing by 100. Under these conditions the chemical shift of benzene is 7.23 ppm. The assignment of multiplets to protons in a complex spectrum is greatly facilitated by a first-order approximation of the spin-spin couplings. Because ortho coupling constants are always 2-4 times larger than meta or para couplings, a ring proton resonance signal will usually appear as a gross singlet, doublet, or triplet, depending on the number of ortho protons to which it is coupled. There are instances, however, when such a procedure cannot be used to assign the protons. In particular, when two protons are only slightly different in chemical shift and are ortho to one another, the multiplets cannot be resolved by first-order rules. In all such cases, we give only approximate observed values. Geometric centers of multiplets were taken as chemical shifts of the corresponding protons. The 6 values are reported to the nearest 0.01 ppm. This is not the limit of accuracy of the instrumentation, but certainly lies well within the limit of the assignment procedure, as geometric centers of multiplets are not, in general, true chemical shifts, An example of the assignment procedure is shown in Figure 1, where the aromatic region of 1,2,4-trichlorobenzene is shown at a sweep width of 100 cps. The assignment of the signals in this case is unambiguous because all the lines are visible and all the line splittings are readily assigned to the ortho, meta, and para couplings. A CLASSIFICATION SYSTEM FOR SUBSTITUTED BENZENES
Let { R1,R2,. . . ,R,} be the set of all possible benzene compounds containing at least one of the n substituents R1, R 2 ,. . . ,R, and at least one ring proton. Let %C,be the number of combinations of n different things taking Y at a timeLe., n ! / r ! ( n - r ) ! . It follows that {R1,R2, . . . ,Rn) can be divided into five distinct kinds of subsets : ZRt = those elements of { R1,Ra,. . , ,Rn} that contain one and only one kind of substituent R r . There are .C1
I6
60
Figure 2. Relationship between the subsets of { R,, Rz,
.
.,R,I
such subsets in { R1,R2,, , . ,Rn]. Each of these subsets contains 11 elements. ZRzpRi = those elements of {Rl,Rz, . . . , R n ) that contain two and only two different kinds of substituent Ri and R,. There are .CZ such subsets in { R J b , . . . ,R,). Each of these subs-ts contains four sub-subsets which we shall designate SIR(,Rj,S2Ri*R,, S3Ri,Rj, and SqRilRjwhere the symbol SZRz,RJ means those members of ZRivR1containing x and only x R z groups. Each sub-subset SIRrsRd,S2R~~R5p S B R i l Rand ~ , S 4 R i , R contains j 18, 23, 12, and 3 elements, respectively. BRrrR5tRk = those elements of {RlrR2,. . ,R,] that contain three and only three different kinds of substituent Ri,Rj, and lit. There are nCa such subsets in { R I , R z ., . . ,Rn}. Each of these subsets contains four sub-subsets which we shall designate SIRi~'lRj,lRk, S2R1,1Rj91Rk, S 3 R r l ' I R J y R k , and SlRi~aRj~2Rk where the symbol S z R r , y R j , R k means those members of ZRirRJzRkcontaining x and only x Ri groups, y and only y R, groups, and z and only z lsk groups. Each subset S 1 R i 81R4*lRk, S z R i ,lR1. S 3 R f s l R j , l R k , and S 1 R L 2 R 1 ~ 2 R k contains 10, 16,10, and 16 elements, respectively. Z R i e R j , R k R z = those elements of { R l ,Rz, . . . ,R,} that contain four and only four different kinds of substituent R2,RI,RK, and R I . There are .C4 such subsets in IR1,R2,, . , , R n ] . Each of the subsets contains two subsubsets which we shall designate SIR'~lRfyRk~lR1 and S 2 R " l R j ~ l R k ~ lz, n where the symbol SZRZ,lRJ~lRk~lR~ means those members of Z R f , R j , R k R l , containing x and only x Rr groups, and one and only one of each other group. Each sub-subset contains 30 elements. ~
VOL. 39, NO. 13, NOVEMBER 1967
e
1587
Table I. A Comparison of the Total Number of Compounds and Unique Protons in Various Sets { R1,Rz, ,R,} No. of kinds of No. of No. of unique substituents, It compounds, N protons, P 19 1 11 134 2 78 3 337 54,3 4 1,074 1,623 5 2,785 3,995 8,574 6 6,236 16,639 7 12,523 29,888 8 23,132 50,499 9 39,999 81,190 10 65,570
R
. ..
5,104,177,100
100
0
Q
b
b C
I Let 6" be the chemical shift (on the 6 scale under standard conditions) of benzene and &, &, and & be the chemical shifts of the ortho, meta, and para protons, respectively. Then one defines the indirect effects of R as follows: &R
=
A,/ + C R - o r t h o =
5,227,332,580
AmR = 6" -
60
- 6,
(5)
6b
APR = 6" - 6, elements of { R1,Rt, . . . ,Rn} that contain five and only five different kinds of substituent Rd,Rj,Rk,R2,and R,. There are .C5 such subsets in {Rl,R2,. . , , R n ] . Each of these subsets contains 60 elements, The significance of this classification system for substituted benzenes stems from the fact that 12 and only 12 different kinds of subsets are required, and that all substituted benzenes that contain at least one ring proton must fall into one of these subsets. Furthermore, by simple addition of the number of elements in each type of subset, one derives at once that the total number of compounds N in any set {R1,R2, . . . ,Rn} is given by : Z R ( ~ R ~ ~ R k ,= R ~those ~Rm
N
=
11,Cl
+ 5G,Cz + 136,c3 + B5OnC4 + 60,Cc.
(1)
(4)
(6)
Because the direct effect of R, C8-+ortho, can never be separated from the true ortho constant of R , A,' we choose the sum, A,' CR-+ortho, as the practical ortho constant of R and shall use it in the remainder of this paper. This operational definition of ARis not without its problems; not all mono-substituted benzenes possess ortho, meta, and para protons sufficiently different in chemical shift to allow an interpretation of the spectrum. For at least one substituent R1, however, such an interpretation can be made. The values of AiR2 can then be obtained by examining compounds containing both substituents R1 and Rz. An operational definition of the two crowding constants, CR1vR-oreho and CR2,R1,R--rortho, can be obtained from the measured chemical shifts in the corresponding di- and trisubstituted benzenes :
+
Moreover, if one counts the number of unique protons in each subset, one derives a similar expression for the total number P of unique protons in any set { R I , R ~. ,. , . ,Rn ] :
P
= 19nC1
+ 96nC2 + 198nCa + 18OnC4 + 60,C.~
(2)
A summary of the total number of compounds and unique protons in various sets f R1&, . . , ,R, } is given in Table I. The relationship between the various types of subsets is illustrated in Figure 2. The total number S of subsets in any set { R1,R2,, . , ,R,] is given by: S = ~ C I 4nCz
+ IO,C3 + 5nC4 f ~
C S
(3)
Ill
I1
Let &a be the chemical shift of the "a" proton above and let Then one defines the two crowding constants as follows: &, be the chemical shift of the "b" proton.
DEFINITIONS
Each and every ring proton in a substituted benzene is influenced by a characteristic indirect effect of each and every substituent on the ring. This characteristic indirect effect is one of three different types for each substituent R , depending on the proton's position on the ring relative to R: ortho constant: AOR;meta constant: AmR;para constant: APR. In addition to the characteristic ortho constant, each substituent on the ring also affects ortho protons by a characteristic direct effect. This direct effect is one of three different types for each substituent R, depending on the number of other substituents adjacent to R: isolated crowding constant: CR+ortho; duo crowding constant: CR1,R-+ortho; trio crowding where R1(if any) is ortho to R and constant: CR28R1,R-+ortho, R2(if any) is ortho to Rl. An operational definition of the indirect effects can be obtained from the measured chemical shifts in the corresponding monosubstituted benzene : 1588
*
ANALYTICAL CHEMISTRY
The presence of a fourth group adjacent to the third group in polysubstituted benzene does not produce a detectable crowding effect. Its indirect effect, however, must be included. Thus, in the tetrasubstituted compound:
E the chemical shift of the "a" proton is given by:
6, = 6"
- &R - AmR1- A,% - AmRa- CRptR1.R-ortho
(9)
Table 11. Effects of Substituents in the Set {OH, C1, Me} Substituent effects," ppm Substituent constants R = O H R=C1 R=Me Indirect effects: AoR +0.50 -0.02 +0.21 +O.ll $0.03 + O . l l AmR APR CoH$R' Ortho
Direct effects:
C C l r R - ortho
C M e , R - ortho COH,OH,R- ortho ortho CMe,Me,R- ortho COH,Cl,R- ortho
CMe,Cl,R-
Sandwich effects: SOHSCI-
-0.14
Ri*
-0.03 -0.03
The sandwich effect, SR1-+-"2, may be described as a diamagnetic anisotropy correction factor for the presence of both substituents simultaneously. Thus, the distance between RI and the proton is different when the proton is also ortho to Ro. Although this physical interpretation of the three kinds of substituent effects is in no way necessary to apply the additivity principle in predicting chemical shifts, it does afford a convenient memory device while performing the calculations. The prediction scheme as presented here does not work for all combinations of substituents on a benzene ring. We have neglected two very important factors in the interaction of substituents with the ring, namely, the perturbing influences of substituents on each other. The agreement between calculated and experimental values reported in this paper shows that this is certainly valid for the substituent combinations considered here. However, in all cases that we have investigated in which more than one strong donor or acceptor is present on the ring simultaneously, the agreement is much poorer. The same is true when some of the substituents on the ring are unusually bulky. We, therefore, propose that the indirect effects of strong donors or acceptors will be perturbed by the presence of other strong donors or acceptors on the ring. Furthermore, we propose that the indirect effects of any substituent which is ortho to a bulky substituent will be perturbed by the bulky group. We call the former effect indirect perturbation factors and the latter direct perturbation factors. In physical terms we might describe the indirect perturbation factor as a measure of the competition between two strong interactors for interaction with the ring. The
-0.18
-0.01
-0.13
-0.12 -0.10
*
-0.09
-0.30
ortho
-0.05 -0.11
-0.25
* * * * *
C O H , > I e , R - ortho CCl,?dle,R- ortho C C I , O H , R - ortho C X e , C H , R - ortho
+0.19 -0.07 -0.11 -0.05
+0.08
*
CCLC1,R'
A PHYSICAL INTERPRETATION OF THE SUBSTITUENT EFFECTS The indirect effects, AsRi(s is ortho, meta, or para), are adequately described by the well known mesomeric and inductive electron displacement mechanisms (13). Thus, an increase in electron density at the ortho and para positions is expected to increase the shielding of the ortho and para protons and their chemical shifts will move toward higher field. The direct effects, CRjtR$--tortho and CRk,R,,Ri-ortho are described adequately by a magnetic anisotropy effect of the substituent Ri. Thus the local magnetic susceptibility effect of the substituent Rc might be acutely sensitive to the distance between R1 and its ortho proton. This distance, in turn, is dependent on the number and nature of the groups adjacent to
+0.41 -0.12 -0.24 +0.04
-0.07 -0.15 -0.10
*
-0.15 -0.15 -0.04 -0.13 -0.22
cR
0.00 -0.02
cR
-0.04
,..
*
*
*
SJb+ c R ... ... -0.04 Referred to benzene, 6" = 7.23 ppm; (+ = upfield, - = downfield). * Not evaluated (appropriate compounds not available or not soluble in CCle). a
In addition to the characteristic indirect and direct effects, each substituent pair which possesses a common ortho proton exerts another influence on that proton. This effect, called the sandwich constant, SR~"R2, is characteristic of the substituent pair, and may be operationally defined from the disubstituted benzene :
9 SR1--R2
=
60
-&
-
summed over all substituents ortho to the rth proton, and R, and R,' are both ortho to the rth proton.
- AoR2
(10)
An extension of Diehl's additivity principle ( I ) yields the following expression for the chemical shift of the rth proton in a polysubstituted benzene : 6 - 6 0 - C A R < - X C R j - o r t h o - SR,--R,'
(11)
T -
where 6' is the chemical shift of benzene (7.23 under our conditions), i is summed over all substituents on the ring, j is
~
Table 111. Comparison of Observed and Calculated Ring Proton Chemical Shifts in the Subset ZlOH Compound Qbsd 6, ppm Calcd 6, ppm Difference, Calcd
.GC
a
a
a b c
= 7.11 = 6.80 = 6.70
~~~
(13) C . K. Ingold, "Structure and Mechanism in Organic Chemistry," Cornell University Press, Ithaca, New York, 1953, p. 61.
a = 6" b = 6' c = 6'
- AmoH = 7.12 - ApOH = 6.82 - AoOH = 6.73
a
- AmoH - ADcH = 6.71 - &OH - &OH - COH,OH+ortho
- Obsd
$0.01 $0.02 +0.02
b
a = 6.72 b = 6.72
a
=
b =
6' 6 0
~
6.74
$0.01 $0. 02
~~
VOL. 39, NO. 13, NOVEMBER 1967
1589
Table IV. Comparison of Observed and Calculated Ring Proton Chemical Shifts in the Subsets ZCl and x = C?! X = Me Obsd Calcd Obsd Calcd Proton 6 , pPm 6, ppm 6 , ppm 6 , ppm a b C
-7.2 -7.2 -7.2
7.25 7.20 7.15
-7.1 -7.1 -7.1
7.02 7.12 7.04
a b
7.39 7.14
7.37 7.12
6.96 6.95
6.96 6.93
a C
7.33 7.17 7.17
7.31 7.17 7. I7
6.85 6.82 7.00
6.85 6.83 7.01
a
7.22
7.22
6.91
6.91
a b
7.33 7.08
7.32 7.09
6.82 6.82
6.82 6.82
a b c
7.44 7.13 7.35
7.43 7.14 7.34
6.78 6.74 6.86
6.79 6.72 6.85
a
7.23
7.23
6.64
6.66
b
a
7.28
7.29
6.72
6.71
a
*
7.38
6.65
6.65
a
'7.54
7.55
6.73
6.73
a
7.53
7.53
6.64
6.64
* Compound not available. direct perturbation factor is described simply as a steric hindrance factor on this interaction with the ring, although other interactions are not excluded-e.g., hydrogen bonding. This particular case is discussed below. We have tried to avoid in this paper all subsets of {R1,R2, . . ,R,] which contain more than one strong interactor and all subsets which contain unusually bulky groups. Our purpose here is to demonstrate the validity of these rather simple ideas. Further work can be concerned with refinements and extensions to achieve more general validity. ~
APPLICABILITY OF THE SUBSTITUENT EFFECTS Subset SRf. Each subset SR*requires 6 constants for the prediction of 19 unique proton chemical shifts in 11 compounds : & f i t , A,%, &Rd, CR,,Ri-Ortho CR,PQi8Rtdortho, and SRi--Ri. Thus, for lid = Rl, R2,and Rs, 18 constants are required for the prediction of 57 shifts in 33 compounds. 1596
ANALYTICAL CHEMISTRY
Subset SIRi,Rj. Each subset SlR"'j requires 6 additional constants for the prediction of 39 chemical shifts in 18 additional compounds: C R i , R j - o r t h o C R j , R p o r t h o C R j , R j , R j - o r t h o CEj,Ri,Rj-artho C R j 3 R i , R p o r t h o , and SRt++-RI. Thus, for ( f i , , R f ) = (R1,R2),(R1,R3),and (Rz,R3),18 additional constants are required for the prediction of 117 chemical shifts in 54 compounds. Subset S2R"Rj,Each subset S2Rf,RJ requires 3 additional constants for the prediction of 38 chemical shifts in 23 additional compounds: CRisRiaRj-rortho, C R i , R j s R i * ~ r t h o , and CRi,R@i-~rtho, Thus for (R&) = (R1,R2), (R1,R3), and (R2,Ra),9 additional constants are required for the prediction of 114 chemical shifts in 69 compounds. Subset SIR~~lRJ~lRk. Each subset SIRfslRj$~Rfi requires 6 additional constants for the prediction of 30 chemical shifts in 10 additional compounds: C R i ~ R j ~ R k * o ' t h o , CRj,Ri,Rk-O'tho C R i , R h , R j + o r t h o C R b , R i , R j - m r t h o C R j , R k , R i - a r t h o , and C R h , R j , R j - o r t h o , In no other subsets are additional constants required for the prediction of chemical shifts. Therefore, for the set {Rl,R 2 , R 3 ) ,a total of 51 constants is required to predict 543 chemical shifts in 337 compounds. Extending the above procedure, one readily derives the following expression for the total number K of constants required to predict all the chemical shifts in any set {I?&, . . . ,R,}:
APPLICATION OF THE METHOD TO THE SET (OH, CI, Me) To test the method, we determined as many as possible of the appropriate substituent effects in the set {OH, C1, Me), where Me = the methyl group. Compound availability and CCld solubility precluded the evaluation of 11 of the 51 constants. The values of the substituent effects are given in Table 11. For most of the substituent effects several compounds were used to obtain a best fit value, while for one or two effects only one compound was available. The success of the method, however, justifies using one compound to predict the chemical shifts in several others. Only two of the available members of E O H are sufficiently soluble in CCl, to yield an NMR spectrum on the HA-100. The observed and calculated chemical shifts of both are given in Table I11 along with illustrations of the calculation procedure. Of the 19 unique proton chemical shifts in SOH, 15 can be predicted from the constants given in Table II. Four of the shifts cannot be predicted because the trio crowding constant CoH~oH~oH-or~ho has not been evaluated. Only 10 of the 11 members of 2'' are available in our laboratory, A comparison of the observed and calculated chemical shifts are shown in Table IV. The agreement between calculated and observed shifts is excellent. The missing compound is included with a prediction for its chemical shift. All 11 methyl benzenes (Pe) are available and are shown in Table IV. The calculated values are again in excellent agreement with the observed values. A comparison of observed and predicted chemical shifts in cl, SloHshfe, and S I C 1 * - \ l e ,is given in Table V. the subsets SloH The agreement is within 0.02 ppm for all but six of the protons. All six of these protons are para to a chlorine atom that is ortho to the OH group. Although we have avoided the introduction of substituent-substituent perturbations in this paper, it is interesting to note the effect of adding a simple perturbation due to hydrogen bonding. Let H p c l* * HO be the correction term to be added to Apcl when the chlorine substituent is perturbed by hydrogen bonding. Then, if
Table V. Comparison of Observed and Calculated Ring Proton Chemical Shifts in the Subset
Compounds
Proton
7.21 6.79 7.04 (7.10) 6.94
6.98 6.70 6.95 6.58
6.98 6.71 6.93 6.58
-7.1 -7.1 -7.1 7.25
7.10 7.04 7.01 7.24
d
6.77 6.84 7.09 6.63
6.77 6.84 7.09 6.65
6.55 6.61 6.99 6.52
6.55 6.61 7.01 6.54
-7.1 6.93 -7.1 -7.1
7.07 6.94 7.09 7.06
a b
6.68 7.13
6.70 7.14
6.60 6.90
6.62 6.91
7.15 7.00
7.14 6.99
6.96 7.07 6.87
6.96 7.01 (7.07) 6.87
6.58 6.80 6.42
6.59 6.82 6.44
*
7.29 7.10 6.90
7.27 7.06 (7.12) 6.91
6.79 6.73 6.46
6.81 6.72 6.47
* * *
6.93 6.80 7.13
7.19 6.81 7.00
7.18 6.81 7.02
6.87 6.51 6.40
6.87 6.50 6.40
7.01 6.84 7.07
6.99 6.83 7.06
7.19 6.74
7.15 (7.21) 6.76
6.83 6.60
6.83 6.61)
* *
6.94 6.93
6.89 7.24 6.62
6.89 7.26 6.62
6.48 6.83 6.43
6.49 6.85 6.43
* *
7.01 6.93 6.95
6.68 6.92
6.69 6.90
6.34 6.44
6.36 6.44
* *
6.88 6.77
*
6.71 6.33
* *
6.79 6.97
C
d
@ Ia C Y b
ba&a
Y
b
a b C
C
a b C
a b
be?&
Y
C
a b
b
X, Y = OH, Me X, Y = C1, Me Obsd 6, (ppm) CaIcd 6, ( p w ) Qbsd 6, kwn) Calcd 6, (ppm)
7.23 6.77 7.12 6.94
a b b
X, Y = OH, C1 Qbsd 6, (ppm) Calcd 6, (ppm)
C
a b
b a b C
* x
;x
i
6.90 7.08
Y
a b
b
a
Y
a b
* *
a
*
Y
*
x
7.02 6.91
6.41 6.25
6.26
6.42
* *
6.90
a b
* *
6.93 7.07 (7.13)
6.50 6.70
6.48 6.72
* *
6.83
a b
7.40 7.12
1.39 7.12
6.73 6.35
6.75 6.34
* *
6.87 7.00
a
7.24
7.16 (7.22)
6.64
6.66
*
6.80
a
*
6.84
6.34
6.35
*
6.88
a
*
7.06
*
6.25
*
6.90
b
Y
7.21 (7.27) 6.84
t
t
Y
Y
Y
Y (Continued)
VOL. 39, NO. 13, NOVEMBER 1967
* 1591
Table V.
(Continued) X , Y = OH, Me Calc 6, (ppm Obs 6, (ppm) Calc 6, (ppm)
X, Y = OH, C1
Compounds
Proton
Obs 6, (ppm)
a
7.38
a
*
X, U =C1, Me Obs 6, (pprn) Calc 6, (pprn)
7.31 (7.37)
*
6.65
*
6.76
6.99
*
6.40
*
t
* Compounds not available. t Necessary substituent effect has not been evaluated.
hDC * 1 Ho . = -0.06 ppm, all six protons are brought in line
CONCLUSIONS
with the rest of the table. The corrected values are given in parenthesis in the table. A comparison of observed and predicted chemical shifts in and S2c1,Me, is given in Table VI. the subsets S 2 0 H , C 1 , SZoNaMe, I n some of the compounds, the hydrogen-bonding factor H p C 1 .. Ho was used to obtain a corrected value which is given in parentheses in the table. Not all the members of these subsets are shown in Table VI. Table VI1 shows some observed and predicted data for a few miscellaneous subsets of the set { OH,Cl,Me}.
Of the 543 possible unique chemical shifts in the set {OH, Cl,Me), 171 have been observed and predicted to good accuracy by the application of 40 empirical constants. Of the 372 remaining shifts, 222 can be predicted from the same 40 constants and some of these predictions have been illustrated. The success of the method indicates that 11 more constants can be evaluated from at least 8 more compounds and the entire remainder of 150 unique chemical shifts can be predicted.
Table VI.
Compound
Comparison of Observed and Calculated Ring Proton Chemical Shifts in the Subsets S F Y X, Y = Cl, Me X , Y = OH, C1 X, Y = OH, Me Proton Obsd 6, ppm Calcd 6, ppm Obsd 6, ppm Calcd 6, ppm Obsd 6 , ppm Calcd 6, ppm
* * *
6.68
* * *
6.60
-7.0 -7.0 7.25
7.03 7.01 7.25
C
6.80 6.71 6.71
6.78 6.73 6.11
* * *
6.56 6.50 6.63
7.20 6.92 7.24
7.19 6.91 7.26
a b
* *
6.93 (6.99)
* *
6.82
t
7.21 6.98
7.21 6.98
a b C
6.44 7.08 6.29
6.44 7.10 6.29
* * *
6.08 6.87 6.21
7.31 7.08 7.08
7.30 7.07 7.06
a
*
* I#
6.04 6.14
7.12 7.00
I . 12 6.99
a b C
a b
=a
b
a
Y
1’ .f
I
t
b
*
6.15 6.36
a
6.66 7.22
6.65 7.23
* *
5.93 6.77
* *
7.29 7.01
b
C
6.75 6.58 6.81
6.73 6.54 (6.60) 6.83
* * *
6.51 6.43 6.47
7.17 7.05 7.22
7.15 7.03 7.21
a
6.96
6.94
0
6.36
7.16
7.14
b
P a
be&
t
x X X * Compounds not available. t Necessary substituent effect has not been evaluated.
1592
ANALYTICAL CHEMISTRY
Table VII. Comparison of Observed and Calculated Ring Proton Chemical Shifts in Some Miscellaneous Subsets of {OH, CI, Me Compound Obsd 6, ppm Calcd 6, ppm Compound Obsd 6, ppm Calcd 6, ppm
1
"I
a
b = 7.27
7.42 7.27
a = 7.08 b = 6.94 c = 6.67
7.08 6.88 (6.94) 6.68
a b c
= = =
7.01 6.96 6.51
7.03 6.95 6.55
a b c
= = =
7.11 6.61 6.51
7.13 6.63 6.51
a = 6.97 b = 6.76 c = 6.53
6.99 6.76 6.54
b@l Me a c1
a = 7.25 b = 6.84
7.26 6.84
MeGCl
a b
1.14 6.93 (6.99)
M;&;l
=
7.42
c1
c1
= =
6.97 6.43
6.97 6.41
a b
= =
6.91 6.72
6.97 6.70
a
=
6.86
6.88
a = 6.47
6.47
a b
= =
7.00 6.50
7.02 6.48
a
=
6.89
6.90
a
=
6.74
6.74
a
c@e b a c1
b
a b
a
= =
7.13 6.99
The introduction of a single additional constant, i.e., a hydrogen-bonding perturbation factor, appears to improve the agreement between predictions and observed values to within 0.02 ppm. This is quite adequate to distinguish ring proton resonances in 100-MHz spectra. The application of the prediction scheme to analyses of aromatic products of chemical reactions is obvious. The extension of the scheme to other substituents is straightforward and simple, because the prediction scheme itself tells exactly which compounds are necessary to predict the chemical shifts in others. In the extension to other substituents, however, one must be on guard for substituent-substituent perturbations, which may or may not be quite large effects. A relationship no doubt exists between the various crowding constants. This is especially true if the diamagnetic aniso-
b HO
e c1
e a
Hiq:e
Me
Me
a6.1 Me
c1
Me
tropy of the substituent ortho to the proton is responsible for the effect. If this relationship can be found, the total number of empirical constants required for the prediction of all the ring protons in any set f R&, . . . ,R,j would be drastically reduced. It is worthwhile, then, to evaluate similar constants for a large number of substituents. ACKNOWLEDGMENT
I thank The0 Hines and T. J. Denson for running the spectra and N. F. Chamberlain, M. s. B. Munson, F. C. Stehling, and W. H. Starnes, Jr., for many helpful ,discussions concerning the effects of substituents.
RECEIVED for review May 5, 1967. Accepted August 21, 1967.
VOL. 39, NO. 13, NOVEMBER 1967
1593
