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10.1002 omr.1270210611

10.1002 omr.1270210611

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13 CNMR Spectra and Structure of Mono-, Diand
Trimethoxyphenylethylamines and
Amphetamines
13 CNMR Spectra and Structure of Mono-, Diand
Trimethoxyphenylethylamines and
Amphetamines

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13
CNMR
Spectra and Structure
of
Mono-,
Di-
and
Trimethoxyphenylethylamines
andAmphetamines
Keith Bailey*
and Donald
Legault
Bureau
of
Drug Research, Health Protection Branch, Health and Welfare, Tunney's Pasture, Ottawa, Canada
K1A
OL2
Carhon-13 and proton chemical
shifts
of
mono-, di- and trimethoxylated phenylethylamines
(PEAS)
and
their hydrochlorides were determined and the signals were assigned and are reported. The data areinterpreted to indicate that the side-chains
of
PEA derivatives and amphetamine
salts
have the amino andaromatic moieties predominantly
trans
(antipenplanar), that 'sandwiched'
OCH,
groups and side-chains areforced out
of
the ring plane and that planar
ortheOCH,
groups have their electron lone pairs orientedtoward the side-chain
and
partially stabilize
gauche
rotamers. It
is
suggested that the location and density
of
electronic charges just outside the aromatic ring
will
significantly affect interactions with putative receptors.
Substituted amphetamines and phenylethylamines(phenethylamines, PEA) have been the subject
of
extensive investigations into structure-activity rela-tionships.',2 Some compounds of this type are en-dogenous and associated with neurotransmission;others, such as mescaline (3,4,5-TMPEA, Fig.
1,
where TMP
=
trimethoxyphenyl), are hallucinogenicand subject to abuse.
'H
NMR spectra of substitutedPEA3 and arnphetamine~~.~ave been reported andinterpreted in terms of changes in the conformationalbehaviour
of
the side-chain. As part
of
a programmeof authentication
of
reference materials for forensicdrug analysis, we determined the I3C NMR spectra
of
the fifteen mono-,' di-6 and trimethoxyamphetamines'(MA,DMA and TMA, respectively). We have nowextended this to an examination
of
PEA
and its mono-,di- and trimethoxy derivatives (MPEA, DMPEA,and TMPEA, respectively; Fig. 1). An examination
of
systematic trends and variations in the data revealseffects that are indicative
of
structural changes relatedto the changes in substitution. The findings may berelevant to studies that have attempted to relate con-formational changes to the differing activities
of
thesecompounds.
RESULTS
AND
SIGNAL
ASSIGNMENTS
Data from the 13CNMR spectra of the PEA deriva-tives are presented in Table
1.
The series is completeexcept for 2,3,S-TMPEA, for which no sample wasavailable. Data from PEA itself and 2,3-DMPEAhave been reported previously.' Assignments of C-a(range 27.0-40.4 ppm) and C-p (range 41.5-43.5 ppm) were made by simple comparison with thecorresponding
amp he tar nine^.^,'
The methoxy signalsappeared between 55.3 and 59.3ppm, except
for
sig-
*
Author
to
whom correspondence should be addressed.
I
R2 Phenethylamine, PEA; R'=R2=HR'Amphetamine, A; R'
=
H,
R2
=
CH,Methoxy-PEA;
R'
=
(OCH,),, R2
=
HMethoxy-A; R'
=
(OCH,),,
RZ
=
CH,
Figure
1.
Structures
of
phenylethylarnines and amphetamines.
nals between 60.7 and
64.1
ppm that arose amongcom-pounds having 'sandwiched' methoxy groups. Assign-ments were tentatively made (Table
1)
by best-fitcomparisons with the MPEA, 2,6-DMPEA, 3,s-DMPEA, 2,4,6-TMPEA and 3,4,S-TMPEA results, asthese are unambiguous.The assignments of the aromatic carbon signals weremade by an internally consistent analysis based
on
approximately additive shielding effects of the sub-stituent groups. Examples
of
the method have beenfully described for corresponding rnethoxyamphet-amine~,~.~ethoxynitrostyrenes' and methylamphet-amines.' Some provisional assignments for closelysimilar chemical shifts are discussed in more detailbelow. Proton decoupling experiments were not help-ful in these cases, because the carbons under consider-ation were either both substituted or the 'HNMRsignals overlapped and could not be assigned.
In
the case
of
PEA itself, the stepwise addition
of
achemical shift reagent (total
85
mg) resulted in pro-gressively increasing downfield shifts
of
the signals as-cribed to C-4, C-33, C-2,6 and C-1
(of
0.49, 0.46,0.21 and 0.21 ppm, respectively), in agreement withtheir proximity to the site of pseudo contact (theamino function"). This confirms the similarity
of
thechemical shifts at C-3 and C-5
(metu
to the side-chain)in
PEA
and amphetamine that was contended previ-o~sly.~his principle" strongly supports the followingassignments tentatively proposed in the amphetamineseries: C-3 and C-S
of
3,4-DMPEA and 3,4-DMA,6
0
iley Heyden Ltd,
1983
CCC-0030-4921/83/0021-0391$03.00
ORGANIC MAGNETIC RESONANCE,
VOL.
21,
NO.
,
1983
391
 
K.
BAILEY AND
D.
LEGAULT
Table
1.
Data
from
the
"C
NMR spectra
of
methoxyphenylethylaminmines"
Signal
PEAPEA.HCI2-MPEA2-MPEA'HCI3-MPEA3-MPEA.HCI4-MPEA4-MPEA.HCI2,3-DMPEA2,3-DMPEA.HCI2,4-DMFEA2,4-DMPEA,HCI2,5-DMPEA2,5-DMPEA.HCI2,6-DMPEA2,SDMPEA.HCI3,4-DMPEA3,4-DMPEA.HCI3,5-DMPEA3,5-DMPEA. HCI2,3,4-TMPEA2,3,4-TMPEA. HCI2,3,6-TMPEA2,3,6-TMPEA-HCI2,4,5-TMPEA2,4,5-TMPEA.HCI2,4,6-TMPEA2,4,6-TMPEA. HCI3,4,5-TMFEA3.4.5-TMPEA.HCI
c-1
139.99139.50128.33127.66141.63141.32131.79131.97133.79133.24120.79120.43129.72129.18116.54115.51132.82132.52142.54142.23126.08125.65122.98122.13120.13119.34109.01108.16135.86'136.34'
c-2
129.05131.67158.08160.33114.90117.45129.97132.94147.88149.52159.00"161.42'152.44"154.88"159.06161.18112.66"115.33"107.25110.17152.50"154.14"148.85"150.31"152.38154.93159.61161.91106.28109.32
c-3
128.75131.85110.71114.42160.15162.15114.24117.33153.16155.2998.99101.79111.81116.OSd104.03107.56149.4Sd151.28d161.30163.43142.84144.48147.52"149.52'98.63101.4290.9894.13153.65155.59
c-4
126.44130.15127.72131.91111.751 15.69158.51160.82111.02115.39159.97"162.64"111.81116.ad127.48131.91148.00d150.1gd98.51101.91152.74c155.35"110.77115.45148.61151.22160.03162.94137.07138.83
c-5
128.75131.85120.73124.01129.66133.18114.24117.33124.07'128.20104.40108.41153.95"156.08"104.03107.56111.93"1 15.09"161.30163.63107.74111.81105.73110.23143.45145.2190.9894.13153.65155.59
C-6
129.05131.67130.75133.67121.46124.50129.97132.94122.62'125.35'131
OO
134.22117.27
1
19.76159.06161.18121.10124.38107.25110.17124.56128.20152.92154.99115.45117.88159.61161.91106.28109.32
ol-CH,
39.8435.3534.4330.5540.0235.4138.5134.5634.1930.0633.4530.0035.1030.6127.2123.2039.6035.0440.3935.5934.1930.0028.3624.1 134.0730.1226.9622.9640.3935.77
B-CH,
43.2443.2441.9042.3943.1843.2443.2443.4242.6942.6942.2142.5742.1542.3941.4842.0143.4843.4243.1843.0642.8842.7542.0342.2142.3942.6941.7842.3343.3043.3055.39
(2)
58.30 (2)55.27 (3)58.18 (3)55.39 (4)58.18 (4)60.73 (2) 55.81 (3)63.65
(2)
58.67 (3)55.51 (2) 55.51 (4)58.42 (2) 58.42 (4)56.18d
(2)
55.87d (5)59.21' (2) 58.85e (5)55.81 (2) 55.81 (6)58.73 (2) 58.73 (6)56.18" (4) 56.06" (3)58.55 (3) 58.55 (4)55.39 (3) 55.39 (5)58.24 (3) 58.24 (5)61.03d (3) 60.85d (2)64.13d (3) 63.77d (2)60.85 (2) 56.42d (3)63.89 (2) 59.09
(3)
56.97'
(4)
56.48' (5)59.27' (4) 59.27' (5)55.81 (2) 55.81 (6)58.61 (2) 58.61
(6)
60.97 (4) 56.30 (3)63.71 (4) 58.97 (3)56.24 (2)58.91 (4)55.w (6)E18.97~
6)
56.W (2)59.79 (5)55.51
(4)
58.36 (4)56.30 (5)58.97 (5)
a
The bases were examined in
CDCI,
and the salts in
DO;
see text for method
of
assignment.
c.d.e
It
is
emphasized that these assignments may be reversed.The numbers in parentheses refer to the assigned position
of
substitution.
C-3
of
2,s-DMPEA and 2,5-DMAh and C-3
of
2,3,6-TMPEA and 2,3,6-TMA.'The position
of
attachment of the methoxy groupswas marked by the lowest field signals. Tentativeassignments (Table
1)
were made by comparisons withthe unambiguous results for the MPEA derivatives andsymmetrically substituted DMPEA and TMPEA de-rivatives. The important assignments of
C-2
and
C-3
of 2,3-DMPEA were based
on
the proposition thatthe shielding effects of the C-2 substituent should beapproximately equal at C-1 and C-3."*8 f
C-2
absorbsat 147.88 ppm and C-3 at 153.16 ppm, the 2-methoxygroup shields C-1 and C-3, relative to
3-MPEA,
by7.84 and 6.99 ppm, respectively; with the reversedassignments the shieldings would be 7.84 and12.27
ppm,
respectively. The former assignment istherefore strongly favoured (Table
1).
The assignments of C-1 and C-4
of
3,4,5-TMAwere proposed
on
the basis of the best fit to predictedchemical shifts, and those for 3,4,5-TMPEA weremade initially by simple comparison. Supporting evi-dence was obtained
by
determining the spectra ofbenzaldehyde (B), 4-methoxybenzaldehyde (4-MB)and
3,4,5-trimethoxybenzaldehyde
(3,4,5-TMB), inwhich the C-1 and C-4 signals were unambiguouslyidentified at 136.74 and 134.67, 130.30 and 164.98,and 132.09 and 144.15 ppm, respectively. Thus, thereis a relative shielding
of
1.79ppm at
C-1
and a de-shielding
of
20.83 ppm at C-4 for 4-MB in comparisonwith 3,4,5-TMB. The corresponding differences forthese signals are 4.07 and 21.44ppm in 4-MPEArelative to 3,4,5-TMPEA (5.28 and 22.65ppm withthe reversed assignments) and 3.64 and 21.50ppm in4-MA relative
to
3,4,5-TMA (5.04 and 22.90 ppmwith the reversed assignments). Similarly, the C-1 andC-4 signals
of
3,4,5-TMB are shifted upfield by4.65 ppm and downfield by 9.48 ppm, respectively,from their positions in
B.
The corresponding differ-ences for 3,4,5-TMPEA
vs
PEA are 4.13 and10.63 ppm (2.92 and 9.42 ppm with the reversed as-signments) and for 3,4,5-TMA
vs
amphetamine are4.20 and 10.63ppm (2.80 and 9.23ppm with thereversed assignments). Similar calculations can bemade from data published for methoxybenzenes."The minimum discrepancies are obtained using theassignments proposed in Table
1,
which are
in
agree-ment with those deduced for 3,4,5-TMPEA.HCl by
Levy
et
al."
SPECTRAL PARAMETERS
AND
STRUCTURAL EFFECTS
Comparisons among isomers and between series re-veal differences which are the net result
of
several
392
ORGANIC MAGNETIC RESONANCE, VOL.
21,
NO.
6,
1983
 
"C
NMR
SPECTRA
OF
METHOXYPHENYLETHYLAMINES AND AMPHETAMINES
Table
2.
Effect
of
y-CH, on chemical
shifts
(ppm)'
Substituentb
C-1
C-216
(ortho)
C-315
(metal
C-4
(para)
C-a
C-p
None
2-
3-4-2,3-2.4-2.5-2.6-3.4-3.5-2.3.4-2,3,6-2.4.5-2.4.6-3.4.5--0.060.1200.30
0
0.0600.13-0.06
0
-
.250.06-0.19
0.18
-0.130.4910.490.0610.670.4310.49
0,5410.54
0.1810.54
0.06f0.67
0.0610.43
0.0610.060.3610.480.4310.43
010.49
0.12/0.060/0.49
0.11/0.11
0.4210.42
010
01-0.06
010
010
0.071-0.06-0.061-0.12-0.061-0.12
010
01-0.06
010
-0.061-0.1901-0.06-0.061-0.06
010
-0.131-0.130.060.120.06
0.12
0.06
0
-0.060.060.060.060.060.060.060.06
-
.066.80 5.166.69 5.176.74 5.106.56 5.116.56 4.986.20 4.986.19 5.716.68 4.986.74 5.106.32 4.856.13 5.466.19 5.046.20 5.536.61 5.047.22 5.28
a
The chemical shift of the
PEA
was subtracted from that of the
A.
Negative signs indicate that upfield shifts result on introducing the
y-CH,.
Italicized figures refer to substituted aromatic positions.Numbers indicate position of
OCH,
attachment.
changes that occur in conjunction; nevertheless,
ex-
amination of the very large data base now availabledoes reveal effects that can be regarded as occurringindependently.
Effects of the
yCH,
Comparison
of
data from amphetamines and the cor-responding phenylethylamines reveals little effect
on
C-1 of the bases (Table 2), but C-1
of
the am-phetamine salts is 0.4-0.8 ppm upfield (y-shieldingeffect"). There is a consistent downfield shift at theortho carbons in amphetamines with a definite grada-tion toward a larger effect at the non-substituted(more accessible) positions. This generalization
sup-
ports the tentative assignments of C-2 and C-6 of2,5-DMPEA (Table
1)
and 2,5-DMA.6 Similar resultswere obtained from the salts (not tabulated). This does
not
have a counterpart in any apparent influence ofortho-OCH, groups
on
the chemical shifts
of
C-y, butseems to be an example
of
the deshielding
6
effect (the
y-CH,
is
6
to the ortho
carbon^).'"'^
There are mod-est (<0.3 ppm) influences trending toward upfield
meta
and downfield para shifts in the amphetamines.Differential effects in the side-chain occur for C-psuch that the amphetamine signal is relatively down-field and/or the phenylethylamine signal relativelyupfield
to
a larger extent than usual in the 2,6-, 2,3,6-and 2,4,6-methoxylated compounds-both bases andsalts. Since there seems to be
no
intermediate effectfor the mono-ortho-methoxylated compounds, the ob-servation might be a reflection
of
C-p being forced out
of
the aromatic ring plane (torsional rotation about thebenzylic bond) by the two flanking
OCH,
groups todifferent extents-presumably greater in the am-phetamine series. There is
no
obvious effect at C-awhich is related
to
this structural change (Table 2).
Effects of
OCH,
groups
The data
in
Table
1
and the data from am-phetamine~~,~an be manipulated to give
a
very largeset
of
data showing the effect
of
ortho-, meta- andpara-OCH, groups
on
one another and
on
side-chainand aromatic carbon chemical shifts. There is littledifference between the chemical shifts of methoxygroups that have one ortho methoxy substituent andthose that have none (ranges 55.81-56.97 and 55.27-56.48 ppm, respectively; Table
1).
Methoxy groupsthat are sandwiched between two ortho substituentsare relatively deshielded by about
5
ppm (range60.70-61.03 ppm; Table
1).
While this manuscript wasin preparation, Knittel and Makriyannis" reporteddata for the OCH3 signals of 2-MPEA and 2,3,4- and3,4,5-TMPEA (mescaline) hydrochlorides
in
D20.
They obtained excellent evidence from relaxation timemeasurements that sandwiched OCH, groups areforced to adopt a conformation in which the 0-CH,bond is essentially perpendicular to the ring plane; this
is
accompanied by downfield shifts of approximately
5
ppm.
Our data, therefore, indicate that
one
orthosubstituent has a minimal effect
on
the overall extent
to
which the methoxy group is in the ring plane.The more notable side-chain data are given in Table
3.
Since methoxylation has little effect at C-y and paramethoxylation has little effect at C-p, these data areomitted. ortho-Methoxylation results in upfield shifts
of
C-a and C-p, and the effects at C-a and C-p arerelatively enhanced and diminished, respectively,when a second ortho-OCH, group is introduced (Table
3).
Analogous results were found for methylation in a
Table
3.
Effects
of
methoxy substitution on chemical
shifts
of
side-chain carbon signals'
ortho
Methoxylation:
210 2.313
C-a
-5.52-5.41 -6.01 -5.83
c-p
-1.33-
1.34
-0.48-0.49
meta Methoxylation:
C-a
+0.12+0.18 -0.37-0.24
para Methoxylation:
C-a
-0.91
-
.33
-0.61
-
0.48
310 2.312
C-p
-0.12-0.06 +0.73+0.79410 2.4122,414-5.22-4.56-1.33- 1.032,512+0.18+0.67+0.06+0.253,413-0.48- 0.422,513 2,612-5.46-4.92 -7.72- 7.22-1.15-1.09 +0.12-0.423,414 3,513+0.55+ 1.09
+0.37+0.37
-0.06+ 0.24
0.000.00
2,3,4/2,3 2.4.5125-0.24
0.00
-1.04-
1.032.3.413.4
-5.77-
5.41-0.73-0.602.3.412.40.00+0.24+0.54+0.672,4,6/2,6-0.24 0.25
-
2.3.513.5 2,3,6/2.3 2.4.513.4 2.4.612.4-5.71b -6.26-5.83-6.02-5.53 -7.35-6.99
-0.ab
-0.31-0.66-1.03- 1.09 +0.12-0.432.3.512.3 2.3,5/2.5 2.3,6/2,6 2.4.512.4+0.67b +O.lZb +1.09+
1.15
+0.25+0.12
O.OOb
+0.67b
+0.30+
.55
+0.26+
0.18
3,4513.5
43.12
0.00
"Values in italics are for
PEA
derivatives, the remainder for amphetamines; the symbolism
210.
etc., indicates that the chemical shift
of
theunsubstituted compound
('0')
was subtracted from that
of
the
2-OCH,
compound
('2')
and
so
on. Positive and negative signs indicate that downfieldand upfield shifts, respectively, result from the substitution.
2.3.5-TMPEA
not available.
ORGANIC MAGNETIC RESONANCE,
VOL. 21,
NO. 6, 1983
393

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