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Detection of Hindered Rotation and Inversion by NMR Spectroscopy.

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5. Conclusion
The type of immune response induced in higher
animals by an antigenic stimulus depends primarily on
biological factors, of which only the genetic factors
have been mentioned here. However, the chemical and
physical nature of the antigen, as well as the dose and
the method of administration, also play an important
part. These factors, the combined effects of which are
not yet clear, lead either to preferential formation of
circulating antibodies and stimulation of cellular immunity or to specific tolerance. Selected examples have
been presented to show that not only the investigation
of the biological principles but also the study of the
antigens themselves, particularly with the aid of synthetic antigens, can contribute to a better understanding of these processes. This discussion was restricted
mainly to the aspect of antibody formation. However,
mention should a t least be made of the use of synthetic
polypeptide antigens, and polypeptide derivatives of
proteins for the study of immunological tolerance ‘991,
the competition of determinant groups 1261, and the
localization of radioactively labeled antigens in lymphatic tissue [84,1001.
[99] I . Schechter, S . Bauminger, M . Sela, D . Nachtigal, and
M . Fellman, Immunochemistry I , 249 (1964); S . Bauminger,
I . Schechter, and M . Sela, Immunochemistry 4 , 169 (1967);
S . Baurninger and M . Sela, Israel J. Med. Sci. 5 , 183 (1969);
G. A . Theis, I . Grenn, B. B e n a c e r r f , and G . W. Siskind,
J. lmmunology 102, 513 (1969).
[loo] J . H . Humphrey, B . A . Askonas, I . Auzins, I . Schechter,
and M . Sela, Immunology 13, 71 (1967).
The wide use of synthetic antigens in the study of immunological problems is based primarily on their suitability as model substances. Our interest, however, is
ultimately in the function of natural antigens. Only in
rare cases have serological cross-reactions so far been
observed between synthetic polypeptide antigens and
natural antigens (see Section 4.1.6). With a more
precise knowledge of the structure of natural antigens,
however, it will become increasingly possible to synthesize antigens in such a way that they have certain
determinants in common with the natural products.
Whereas this aim was achieved by GoebelE541 as early
as 1939 for polysaccharides, attempts to do the same
with protein antigens have only recently been successful. Thus antigens containing the serologically important C-terminal hexapeptide sequence of the coat
protein of tobacco mosaic virusrloll and a large polypeptide loop of lysozyme r1021 have been prepared.
Antigens of this type allow specific immunization
against certain sub-units of natural antigens, and,
consequently hold out hopes of useful practical applications.
I am grateful to Prof. Dr. D . Rowley and to Prof. Dr.
W. Volk for critical perusal of the translated manuscript.
Received: June 9, 1969
[A 745 IEI
German version: Angew. Chem. 82, 202 (1970)
Translated by Express Translation Service London
. .~..
. ..
~
[loll F. A . Anderer and H . D . Schlumberger, Biochim. biophysics Acta 97, 503 (1965).
[lo21 R . Arnon and M . Sela, Proc. nat. Acad. Sci. USA 62, 163
(1969).
Detection of Hindered Rotation and Inversion by NMR Spectroscopy[11
By Horst KesslerI*I
Rotations and inversions in organic molecules are readily recognizable from the temperature dependence of the N M R spectra. The study of the effectsof substituents on the
activation barriers of such processes permits fhe elucidation of reaction mechanisms, and
the stability limits of isomers can also be determined. The knowledge of the stability
limits is necessary for the specific synthesis of stable rotamers and invertomers.
1. Introduction
Modern organic stereochemistry has two aspects, one
static and the other dynamic. The reactivity of a molecuIe is not determined purely by the predominant steric
arrangement; the possibility of assuming other conformations that are more favorable to the reaction is
often an important factor.
N M R spectroscopy provides the chemist with a means
of studying intramolecular movements with activation
energies of 5 to 25 kcal/mole1*-41. Processes of this
type are so fast that the resulting isomers cannot be
separated at room temperature. On the other hand,
~
[21 G . Binsch: Topics in Stereochemistry, Interscience, New
[*I Priv.-Doz. Dr. H. Kessler
York 1968, Vol. 3, p. 97ff., a n d literature cited therein.
[3] Ring inversion processes: J . E . Anderson, Quart. Rev.
(chem. SOC.London) 19, 426 (1965); F. G. Riddel, ibid. 21, 364
(1967).
Chemisches Institut d e r Universitat
74 Tiibingen, Wilhelmstrasse 33 (Germany)
[ l ] Part 1 3 of a series of reports on t h e detection of intramolecular mobility by N M R spectroscopy. For Part 12see[109].
[4] Valence isomerizations: G. Schrdder and J . F. M . O t h , Angew. Chem. 7Y, 458 (1967); Angew. Chem. internat. Edit. 6,414
(1967); E . Vogeland H . Giinther, Angew. Chem. 79,429 (1967);
Angew. Chem. internat. Edit. 6, 385 (1967).
Angew. Chem. internat. Edit.
Vol. 9 11970) / No. 3
219
they are too slow for investigation by I R and Raman
spectroscopy or by dielectric constant measurements [51.
The present article describes the application of N M R
spectroscopic methods to the study of rotations. In
view of their close relationship with rotations, inversions are also briefly discussed. Processes in which
parts of a molecule (e.g. in cycloolefins[~l)rotate by
simultaneous rotation about two or more bonds are
not considered, and rotation in a 171 and K metal complexes 181 is also excluded.
2. Theory
2.1. General
In the rotation about a bond in a molecule, there are
certain energetically favored positions of the substituents. For example, a planar arrangement is most
favorable for the substituents on two carbon atoms
joined by a (p-p)x double bond. The dependence of
the energy on the angle of rotation about the double
bond is shown in Figure 1.
rapid thermal isomerization, the rate constant kr of
which is related t o AC+ in accordance with the Eyring
equation [eq. (1)] [91.
kr
k~ T
__ exp
h
=
*
(- <F)
AG
(1)
( k B = Boltzmann’s constant, h = Planck’s constant,
R
=
gas constant, T = absolute temperature).
AG#
= 4.57
T (10.32
+ log T/kr
(la)
This situation is again illustrated in Figure 2, in which
the rate constant kr of an isomerization increases from
left to right. The free enthalpies of activation AC* at
room temperature as calculated from eq. (1) are also
shown. Separation of isomers is possible if the mean
lifetime is of the order of a few hours or more. This
corresponds to kr values of less than lo-4sec-1 or
AC* values greater than 23 kcal/mole (at 25 “C).The
N M R method (see Section 2) covers a range extending
downward from the vicinity of the separation limit,
which is difficult to study by other methods.
Separation at room temperature
possible
-
AG*
Ikcal/molel
L
LO
log k
-16 6
impossible
-
i
30
-11
- 9.3
-19
-
5L
W
microwave
direct equrlibratior!
......... ...
.
fiash
photolysis
... .. ..
NMR
I
Fig. 2 .
0
10
I
Possibilities for the detection of intramolecular mobility.
Isomerization of this nature can be followed particularly readily by N M R spectroscopy when AGO is
small, i.e. according to
@+
Fig. 1. Energy profile for rotation about a double bond. For A and B
cf. ( I ) .
To convert the isomer A into the isomer B, it is necessary to supply the free enthalpy of activation AC&.
The energy
that must be supplied for the reverse isomerization differs by AGO from &,+,. The
magnitude of the free enthalpy of activation determines the rate of the thermal isomerization. If AC*
2 23 kcal/mole, the isomers are stable at room temperature; smaller AG* values lead to more or less
[5] S. Mizushima: Structure of Molecules and Internal Rotation. Academic Press, New York 1954; H. Dreizler, Fortschr.
chem. Forsch. 10, 59 (1968).
I61 C. M. Whitsides, B. A . Pawson, and A. C . Cope, J. Amer.
chem. SOC.90, 639 (1968); G . Binsch and J . D . Roberts, ibid. 87,
5157 (1966); S . Dev, J . E . Anderson, V . Cormier, N . P . Damodaran, and J . D . Roberts, ibid. 90, 1246 (1968); I . C. Calder, Y.
Gaoni, P . J . Garratt, and F. Sondheimer, ibid. 90, 4954 (1968);
G . Schroder and J . F. M . Oth, Tetrahedron Letters 1966, 4083.
[7] G. M. Whitesides and J . S . Fleming, J. Amer. chem. SOC.89,
2855 (1967).
[8] R . Cramer, J. Amer. chem. SOC. 86, 217 (1964); A. R.
Brause, F. Kaplan, and M . Orchin, ibid. 89, 2661 (1970).
220
AG0
=
--RT In ([A]/[B])
(2)
when the concentrations of the isomers are comparable.
The conditions for N M R spectroscopy are particularly
favorable when R1 = R2 in ( I ) . A and B are then
chemically identical [*I. In the N M R spectrum, how-
B
A
(1)
[9] A. Frost and R . Pearson: Kinetik und Mechanismus homogener chemischer Reaktionen. Verlag Chemie, Weinheim/Bergstrasse 1967.
[*] A and B are “degenerate isomers”, for which we propose
the term “topomers”. A and B differ by the exchange of diastereotopic [ll d] groups, and are therefore diastereotopomers.
T h e process of interconversion would then be called topomerization (diastereotopomerization). The exchange of prochiral [ l l d ]
groups then corresponds to an enantiotopomerization, which
can be followed N M R spectroscopically because of t h e nonequivalence of the two X groups in CX2Y substituents a s prochiral groups. (G. Binsch, E . L . Eliel, and H . Kessler, unpublished).
Angew. Chem. internat. Edit.
/
Vol. 9 (1970)
NO. 3
ever, R1 and R2 are not equivalent if X and Y are
different, and rotation about the double bond accordingly leads to “exchange” of the groups R1 and R2.
“Slow” [*I isomerization leads to two separate signals
for Rl and R2 in the N M R spectrum, while “fast”
rotation gives o n l y one signal with an intermediate
chemical shift (cf. Fig. 3).
dependence of the magnetic non-equivalence. This is
so e.g. in compounds of the type ( 2 ) 111~1.
4
CXZY
=a
mirror image
object
(2)
2.2. Kinetic Evaluation of NMR Spectra
As was mentioned above, the shape of the signal in the
transition region can be used to determine the rate
constants. The theory of‘ line broadening is well developed and has been presented clearly 1121, particularly for simple cases. Several methods of evaluation
are available in practice:
1. By approximation equations.
2. By graphical evaluation of certain spectral parameters.
3. By computer matching of measured and calculated
spectra.
Fig. 3. Temperature dependence of the N M R spectrum as a result of
chemical exchange (uncoupled A B case). For explanations see text.
For thermally induced rotations, the N M R spectra are
temperature dependent in the transition region between “slow” and “fast” rotation, and can be used to
determine the rate constants k,. The activation parameters (AG*, A H * , AS+, Ea) can be found from k,
(see Section 2.2).
A different situation arises when rotation leads to
racemization. The two X groups in CXzY substituents
may be magnetically non-equivalent when the remainder of the molecule (viewed from the direction of
the CX2Y group) is chiral [lo, 111. The intramolecular
rotation can be detected with the aid of the temperature
.
[ * ] “Slow” on t h e N M R timescale means that t h e reaction
rate constant k , 4 xAv/ 1/2 ( A v = signal splitting without exchange) [see eq. (3)]. ‘‘Slow’’ I S to be regarded as a statisticalkinetic description in this context. A slow rotation is one in
which only a small fraction of t h e molecules can overcome the
energy barrier in unit time. T h e actual rotation of t h e individual
molecule, however, is very fast owing to the small moment of
inertia. “Infrequent” would therefore be a better term than
“slow” and “frequent” would then have to be used instead of
“fast”.
[lo] R . S. Cuhn, C . K . Ingold, and V . Prelog, Angew. Chem. 78,
413 (1966); Angew. Chem. internat. Edit. 5 , 385 (1966).
[ l l ] a ) M. L . Martin and G . J . Martin, Bull. Soc.chirn. France
1966, 2117; b) M. van Gorkom and G . E. Hull, Quart. Rev.
(chem. SOC., London) 22, 14 (1968); c ) H . Kessler, Tetrahedron
24 , 1857 (1968); d ) K . Mislow and M. Raban, Topics in Stereochem. 1, 1 (1967); D . Arigoni and E. L . Eliel, ibid. 4 , 127 (1969).
Angew. Chem. internut. Edit. J Vol. 9 (1970)
/ No. 3
A particularly simple situation occurs when two
atoms (or groups) with initially sharp signals of equal
intensity undergo chemical exchange (uncoupled AB
case, see Fig. 3). For evaluation by approximation
equations, parameters such as the line separation
Av 1133, the line broadening b1/2 114.211, and the intensity ratio 10/1~~,
[I51 in the low-temperature case, the
line width bl/z in the high-temperature case [*61, and
the coalescence temperature 1181 are found from the
spectrum. The coalescence temperature is the temperature at which two signals just coincide (see Fig. 3 ) .
The validityof the equations is limited in most cases 1171.
It is relatively easy to obtain the rate constant k, of
the chemical exchange at the coalescence temperature
T,. Ignoring the intrinsic width, we then have:
(Av
=
kc = xAv/]/2
(3)
line separation without exchange)
for the uncoupled AB case[lel [**I.
[I21 A. Loewenstein and T . M. Connor, Ber. Bunsenges. physik.
Chem. 67,280 (1963); C . S.Johnson, Advances Magnetic Resonance I , 33 (1965).
[I31 H. S.Gutowsky and C . H . Holtn, J. chem. Physics 25, 1228
(1956).
[I41 A . Jaeschke, H. Muensch, H. G . Schmid, H . Friebolin, and
A . Munnschreck, J. molecular Spectroscopy 31, 14 (1969).
[15] M . T . Rogers and J . C. Woodhre.v, J. physic. Chem. 66,
540 (1962).
[16] L. H. Piette and W. A . Anderson, J. chem. Physics 30, 899
(1959).
[17] A . Allerhund, H . S. Gutowsky. J . Jonas, and R. A . Meinrer,
J. Amer. chem. SOC.88, 3185 (1966).
[18] J . A. Pople, W. G . Schneider, and H. J . Bernstein: HighResolution Nuclear Magnetic Resonance. McCraw-Hill, New
York 1959.
[**I T h e uncoupled AB case refers to thespectrum o f t w o types
of nuclei (A and B) that a r e not coupled to each other. In the
normal AB case, o n t h e other hand, four lines a r e observed
because of coupling of A with B and vice versa.
22 1
For the coalescence of an AB-type spectrum (to Az),
we have [I91 (disregarding the intrinsic width):
where J is the constant for the coupling between the
nuclei A and B.
Graphical methods 1201 are particularly suitable for
the evaluation, since the intrinsic widths of the lines
and the temperature dependence of the splitting without chemical exchange [17,211 can be taken into account
more satisfactorily.
T h e reason for t h i s is t o be found in t h e k, values, t h e errors
i n which increase with increasing distance from the coalescence temperature. However, only a relatively small temperature range o f from about 20 t o a t most 60 OC is available
for t h e evaluation. T h e gradient of the Arrhenius line, which
is a measure of t h e activation energy Ea, a n d hence also its
intercept o n the ordinate (log A ) are very strongly influenced
by small deviations of the k, values; high Ea values go with
high log A values a n d vice versa. I n a plot o f t h e Ea values
f o r dimethylformamide from t h e literature against the corresponding log A values, all but o n e of t h e points lie on a
straight line passing through t h e origin (Fig. 4).
+
20 t
If the contributions of two rotamers to the equilibrium
are no longer equal (AGO =+ 0), the ratio of the intensities of the bands is not equal to unity (evaluation
e.g. according to 1141). Computers are necessary for
the evaluation in more complicated cases; the shapes
of the curves can then be simulated and compared
with the experimental spectra.
The free enthalpy of activation AG: can be calculated
from the rate constants kr by means of the Eyring
equation (1). The temperature-dependent AG* value
contains the activation entropy AS*. To find the Arrhenius activation energy E a , log k, is plotted against
the reciprocal of the temperature ( A ?= frequency
fat t or) :
k,
=
log k ,
A exp ( - E a / R T )
=
const
.-
(5)
Ea/4.56 T
(5a)
*
The Ea values (or A H = Ea-RT) should be used for
the comparison of compounds, since it does not
contain the temperature-dependent entropy term
TAs*. It has been shown, however, that the E a values
are mostly very uncertain. Thus for dimethylformamide [*I, which has probably been studied more often
by NMR spectroscopy than any other compound, the
literature contains Ea values ranging from 7 to 28 kcaf/
mole and log A values of from 7 to 17[2,231. On the
other hand, the values found for the free enthalpy of
activation AG? from the coalescence temperature
with the aid of equations (1) and (3) all differ by less
than 1 kcal/mole from the average (21.5 kcal/mole) r13,
I S , 23,241.
[19] R . J . Kurland, M . B. Rubin, and W . B. Wise, J. chem.
Physics 40, 2426 (1964).
[20] M . Takeda and E. 0 . Srejskal, J. Amer. chem. SOC.82, 25
(1960); H. G . Schmid, H. Friebolin, S. Kabuss, and R . Mecke,
Spectrochim. Acta 22, 623 (1966).
[21] F. A . L. Anet and A . J . R . Bourn, J . Amer. chem. SOC.89,
760 (1967).
[*I Without solvent; for measurements in solution see [22].
[22] J . V . Hatton and W . G . Schneider, Canad. J. Chem. 40,
1285 (1962); M . L. Blanchard, A . Chevallier, and G . J . Martin,
Tetrahedron Letters 1967, 5057; R . C . Neumann, Jr. and L . B.
Young, J. physic. Chem. 69, 2570 (1965).
[23] a ) G . Fraenkel and C . Franconi, J. Amer. chem. SOC.82,
4478 (1960); b) A . G . Wittaker and S . Siegel, J . chem. Physics
42, 3320 (1965); c ) M . Rabinowitz and A. Pines, J. Amer. chem.
Soc. 91, 1585 (1969); A . Pines and M . Rabinowitz, Tetrahedron
Letters 1968, 3259; d ) F. Conti and W. v. Philipsborn, Helv.
chim. Acta 50, 603 (1967); e) C . W. Fryer, F. Conti, and C .
Franconi, Ric. sci., Parte 11, Sez. A 35, 788 (1965).
1241 A . Mannschreck, A . Mattheus, and G . Rissmann, J. molecular Spectroscopy 23, 15 (1967).
222
/
i 23 bl
0
117(811
L
8
12
16
20
E, Ikcalimolel-
2L
28
Fig. 4. Experimental kinetic d a t a f o r t h e rotation a b o u t the C--N
b o n d in solvent-free dimethylformamide. T h e numbers a r e literature
references, a n d the lengths of t h e lines indicate t h e e r r o r limits. -Ea Arrhenius activation energy, A =- frequency factor [eq. (S)].
Where accurate measurements (such as e.g. in 1211)
covering a fairly wide temperature range are not
available, it is better to avoid a discussion of the
physically accurate but numerically doubtful Ea
values (or AH+ = Ea-RT), and to use the AG? values
instead [17J. The temperature dependence of AG* is
then deliberately ignored, and normal frequency
factors are postulated (low reaction entropies AS*).
This procedure is not problematic above all in the
comparison of similar types of substances. The stability
of isomers at a given temperature i s determined in any
case by AG+.
If it is still desired to determine Ea and AH*, several
methods should be used if possible in order to extend
the temperature range. This can be done in suitable
cases both by the measurement of k, values by the
spin echo method[251 and the double resonance
method described by Forsen and Hoffmann1261 and by
direct equilibration 124,273. Since very few investigations of this nature and reliable line shape analyses
have been carried out so far, the free enthalpies of
activation at the coalescence temperature Tc are used
for discussion in this article. The error in Tc (usually
about f 2 to 5 ° C ) largely determines the error in the
AG? values ( ~ 0 . to
5 4%). Owing to the temperature
dependence of AG+,the coalescencetemperature,which
[25] K . H. Abramson, P . T . Inglefield. E. Krakower, and L . W.
Reeves, Canad. J. Chem. 44, 1685 (1966); P . T . Inglefeld, E.
Krakower, L . W . Reeves, and R . Stewart, Molecular Physics 15,
65 (1968); A . Allerhand and H. S . Gutowsky, J. Amer. chem.
SOC.87, 4092 (1965), and literature cited therein.
[26] S. Forsen and R . A . Hoffmann, J. chem. Physics 40,1189
(1964); Acta chem. scand. 17, 1787 (1963); J. chem. Physics 39,
2892 (1963).
1271 H . S. Gutowsky, J . Jonas, and T . H . Siddall, J. Amer. chem.
Soc. 89, 4300 (1967).
Angew. Chem. internat. Edit. 1 Vol. 9 (1970)1 No.3
can be varied within certain limits by the choice of
the measuring frequency, is given whenever possible.
The rate of intramolecular rotations and inversions,
like that of other reactions, also depends on the solvent
and o n the concentration of the solute. In series of
measurements on various substances, therefore, only
one solvent should be used if possiblel*l. Comparative discussions become increasingly problematic with
increasing dissimilarity of the structures of the compounds and solvents investigated and of the concentrations and coalescence temperatures.
contents and there is only one activation energy. For
methyl groups (R1 = R2 = R3 = H), this has a value of
Ea 5 3 kcal/mole[301, and can no longer be detected
Other methods besides N M R spectroscopy can be
used for the detection of intramolecular rotations [5J.
3. Applications
3.1. General
60
Free rotation about a bond in the molecule may be
sterically and electronicslly hindered. Thus the stability of cis-trans isomers about the C C double bond is so
great because of electronic effects that their rotamers
are described as configurational isomers, though they
are really mostly very stable conformers. Rotation
about a CC single bond (the 6 bond is rotationally
symmetrical) may be sterically hindered, as in the wellknown example of atropisomerism in biphenyl derivatives, but can also be restricted by resonance effects,
which give the single bond partial double bond character.
3.2. Rotations about Single Bonds
3.2.1. C a r b o n - C a r b o n S i n g l e B o n d s
120
180
C
--
0
0
240
300
E
360
Fig. 5 . Energy profile f o r r o t a t i o n in a n unsymmetrical ethane. C , D.
a n d E a r e the stable staggered c o n f o r m a t i o n s a t t h e indicated angles of
rotation.
by N M R spectroscopy. Splitting due to hindered
rotation about the CC single bond is however found
for the fert-butyl group (R1 = R2 . R 3 = CH3)
(Table 1).
In the compounds (7) and ( 9 ) , one should expect
splitting of the fert-butyl signal into three singlets
having relative intensities of 1 : 1 : 1, and in the other
compounds into two singlets having an intensity ratio
of 2 : 7 . The fundamental correctness of these considerations is shown by the low temperature spectrum
of (7a), in which all three methyl groups of the tertbutyl group are separated (Fig. 6 ) [33bl.
3.2.1 .l.
sp3- s p 3 H y b r i d i z a t io n
In the rotation about single bonds between sp3-hybridized carbon atoms as in (3)[281, the heights of the
energy barriers are determined mainly by the steric
hindrance in the eclipsed transition state. The types
of spectrum to be expected for fast and slow rotation
have been discussed by Pople[291.
(3)
With identical substituents R1, R2, and R3, the conformations C, D, and E in Figure 5 have equal energy
I"]This is unfortunately not always possible, owing to the
general properties of t h e solvents (b.p., m.p., solvent power)
and possible absorptions in t h e measurement region.
[28] E . L . Eliel: Stereochemistry of Carbon Compounds.
McGraw-Hill, New York 1962.
[29] J . A . Pople, Molecular Physics I, 3 (1958).
Angew. Chem. internat. Edit. J Vol. 9 (1970) J No. 3
(9)
[30] J . P. Lowe and R. G. Purr, J . chem. Physics 44, 3001
(1966); 0. J. Sovers and M . Karpens, ibid. 44, 3 0 3 3 (1966); J.
Dale, Tetrahedron 22, 3 3 7 3 (1966).
223
Table 1.
1
Cpd.
c
?.‘
(kcallmole)
-- 4-7
(6), R
171, R
=
=
Cpd.
;
3.2.1.2. s p 2 - s p 3 H y b r i d i z a t io n
Ref.
(kcal/mole)
I
[a1
6-8
Br,OCHn
Br
Ref.
1 11 1 1
I
(41
{S), n
I 1 1 ’.: 1
Hindered rotation of tert-butyl groups
I1
1311
;;;;
[321
I
(8)
(9)
(10)
I
9.0
10.1
1341
9.4
[341
1351 [bl
[a] No energy barrier data.
[bl The low temperature process described i n this reference is better
explained by hindered rotation of the tert-butyl group than by an
equilibrium between a chair form and a twist form. Further investigations are in progress.
Rotation about the single bond between sp2- and sp3hybridized carbon atoms can be hindered by bulky
substituents. Hindered rotation attracted particular
interest in two tert-butyl derivatives (12) 1381 and
(13) 1391 of benzene, triarylmethanes (14) 1401, o-disubstituted alkylbenzenes (15) 134,411, and 9-arylfluorenyl compounds (16) 134,421 and (17) 1341.
t -C,Hg
R2
R 3 P R ,
R’
R3
Fig. 6. Aliphatic region in the N M R spectrum of (7a) at -9OOC
(220 MHz) [*I.
The resolution is often not sufficient for complete
separation of all the bands.
Many halogenated alkanes (11) have been studied
mostly by fluorine resonance 1361. The energy differences AGO between the three rotamers are determined by the nature of the substitution.
FmClnBroC-CFpClqBrr
m+r
=
0+3
The activation barriers generally increase with the
size of the atoms [36al, and can be as high as 12 kcal/
mole. Hindered rotation of a C F 3 group has recently
been observed 1371.
1311 J . P . N. Brewer, H . Heaney, and B. A . Marples, Chem.
Commun. 1967, 27.
[32] F. A . L . Anet, M . S . Jaques, and G . N . Chmurny, J. Amer.
chem. SOC.90, 5243 (1968).
[33] a) A . Rieker, N . Zeller, and H . Kessler, J . Amer. chem.
S O C . 90, 6566 (1968); b) A . Rieker and H . Kessler, unpublished.
[34] A . Rieker and H. Kessler. Tetrahedron Letters 1969, 1227.
[35] H . Kessler, V. Gusowski, and M . Hanack, Tetrahedron
Letters 1968, 4665.
[*] We a r e grateful to Dr. W. Brugel, BASF, Ludwigshafen,
for recording the spectrum.
[36] a) R . A . Newmark and C . H . Sederholm, J. chem. Physics
43, 602 (1965); b) J. D . Roberts, Angew. Chem. 75, 20 (1963);
Angew. Chem. internat. Edit. 2, 53 (1963); c) H . S. Gutowsky,
Pure appl. Chem. 7,93 (1963); d ) R . L . Voldand H . S . Gutowsky,
J. chem. Physics 47,2495 (1967); e) T . D . Alger, H . S . Gutowsky,
and R . L . Vold, ibid.47, 3130 (1967).
[37] F. J . Weigert and J. D . Roberts, J. Amer. chem. SOC.90,
3577 (1968).
224
(16), R‘ = R3 = CH,
(17). R’ = R2 = OCH,
The “chemical exchange” of the methyl and methoxy
groups in (16) and (17) also proceeds in principle by
dissociation of the group X. However, this is not
possible in the derivatives with X = H (except in the
presence of basic catalysts). The decrease in AG: in
the order H > O H > C1 appears to be connected with
the bulk of X. The larger X is, the greater is the hindrance in the ground state, and the smaller the energy
difference between the ground state and the transition
state 1341.
3.2.1.3. sp2-sp2 H y b r i d i z a t i o n
Rotation barriers in biphenyl derivatives have so far
been measured in only a few cases (Table 2).
[38] D . T . Dix,G . Fraenkel, H . A . Kurnes, and M . S. Newman,
Tetrahedron Letters 1966, 517.
[39] G . P . Newseref and S . Sternhell, Tetrahedron Letters
1967, 2539.
[40] H . Kessler, A . Moosmayer, and A . Rieker, Tetrahedron 25,
287 (1969)
[41] a) A . Mannschreck and L . Ernst, Tetrahedron Letters 1968,
5939; b) C. A . Cupas, J . M . Bollinger, and M . Huslanger, J.
Amer. chem. SOC.90, 5502 (1968).
1421 E . A . Chandross and C.F. Sheley, Jr., J. Amer. chem. SOC.
90, 4345 (1968); T . H . Siddulf and W. E. Stewart, Tetrahedron
Letters 1968, 5011; Chem. Commun. 1968, 1116.
Angew. Chem. internat. Edit. / Vol. 9 (1970)
/ NO. 3
Table 2.
single bonds often possess partial double-bond character. In such cases, the energy is lowest in the planar
conformations s-cis (cisoid) and s-trans (transoid) [ 5 0 4 ;
however, the activation energy required for rotation
about the central bond is generally not very high.
Some examples are given in Table 3 .
Rotation in biphenyl derivatives
__
Cpd.
CH3
CHzOCOCH,
CH(CH3)z
C(OH)(CH3)2
OCH,
OCOCH,
17.4
20.2
126 1
b24.5
13.7
18.5
-35
127
>200
>I90
-25
+46
[431 [a]
[44] [b]
[45]
[45]
[461
[461
[a] Measured by direct equilibration.
[b] Calculated from the literature data.
AG: increases very rapidly with the size of the residue
R, and can ultimately no longer be determined by
N M R spectroscopy.
Steric hindrance of the rotation about the aryl-CO
bond has been found in benzamides [471, benzophenones[48], and benzilsr481. It is so great in tert-butyl
aryl ketones that the optical antipodes can be separated [491.
Table 3.
Hindered rotation about partial C C double bonds
Rotation about C-aryl bonds is also sterically hindered
in the propeller conformations of triarylmethyl
cations (20) [501. The geometry of the propeller (righthand or left-hand screw) and the position of the substituents R lead to interesting isomerism phenomena.
(23)
17
55
[52]
(26)
12-16
-32
[551
to
+I3
(24)
10-11
-57
[531
(27)
[bl
-
[561
[a] “Frozen in” at -105 “C. No barrier data.
[b] No barrier data.
Steric hindrance of rotation is less common than
“electronic hindrance”. Owing to the participation of
ionic limiting structures such as G in (21), formal
[43] W . Therlackerand H . Bohm, Angew. Chem. 79,232 (1967);
Angew. Chem. internat. Edit. 6, 251 (1967).
AG: increases with increasing difference between the
electron donor and acceptor properties of X and Y.
In compounds of the type (25), therefore, rotation
becomes increasingly difficult in the order X=H <
OCH3 < N(CH3)z. Hindrance of rotation about the
aryl-C bond as a result of opposite polarization (aryl
ring negative, substituent positive) has been found in
ketene aminals [82, 112dl.
[44] W . L. Meyer and R. B. Meyer, J. Amer. chem S O C . 85,
2170 (1963).
[50a] K . Mislow: Einfiihrung in die Stereochemie, Verlag Chemie, Weinheim/Bergstr. 1967, p. 70.
[4S] H . Kessler, unpublished.
[51] W. S . Brey, J r . and K . C. Ramey, J. chem. Physics 39, 844
(1963).
[46] L . D. Coiebrook and J . A . Jahnke, J. Amer. chem. S O C . 90,
4687 (1968).
[47] T . H . Siddall and R . H . Garner, Tetrahedron Letters 1966,
3513; T . H . Siddall and W . E. Stewart, Chem. Commun. 1967,
393; G. R . Bedford, D. Greatbanks, and D . B. Rogers, ibid. 1966,
330; T . H . Siddall and R. H . Garner, Canad. J. Chem. 44, 2387
(1966).
[48] D . Lauer and H . A . Staab, Tetrahedron Letters 1968, 171.
[49] A . G. Pinkus, J . I . Riggs, J r . , and S . M . Broughton, J.
Amer. chem. SOC.90, 5043 (1968).
[50] J . J . Schuster, A . K . Colter, and R . J . Kurland, J. Amer.
chem. SOC. 90, 4679 (1968); R . Breslow, L . Kaplan, and D .
LaFollette, ibid. 90, 4056 (1968).
Angew. Chem. internat. Edit. 1 Yol. 9 (1970) 1 No. 3
[52] H . J . Bestmann, G. Joachim, I . Lengyel, J . F. M . Oth, R .
Merenyi, and H . Weitkamp, Tetrahedron Letters 1966, 3355;
F. J . Randall and A . W. Johnson, Tetrahedron Letters 1968,
2841.
[53] K . I . Dahlquist and S . Forsen, J. physic. Chem. 69, 1760,
4062 (1965).
[54] F. A . L . Anet and M . Ahmad, J . Amer. chem. S O C . 86, 119
(1964); R . E. Klinck, D. H . Marr, and J . B. Stothers, Chem.
Commun. 1967, 409.
[55] F. Knplan and G. K. Meloy, J. Amer. chem. SOC.88, 950
(1966).
[S61 J . Dabrowsky and L . Kozerski, Chem. Commun. 1968,586.
225
a-x rearrangements or CC rotation are discussed for
the isomerizations in x-ally1 complexes 1571.
11.8
In connection with rotations in anions (28)150 and
cations (29) 1591 of the ally1 type, the reader is referred
to the literature.
21.8
3.2.2. C a r b o n - N i t r o g e n S i n g l e B o n d s
17.9
3.2.2.2. H i n d e r e d R o t a t i o n A b o u t P a r t i a l
D o u b l e Bonds
3.2.2.1. S t e r i c H i n d r a n c e of R o t a t i o n
Steric hindrance of rotation about the aryl-N bond is
the reason for the magnetic non-equivalence of the X
atoms in substances of the types (30) to (33). The
rotation is less hindered in amines ( Z = alkyl)[60,61l
than in amides ( Z = COR) [11c,60,62,631 and nitrosamines
( Z = NO) 161,631. The ammonium salts (33) are com-
C-N bonds with partial double-bond character occur
in compounds of the type (38).
(38)
X = CR, N
Y = CRR‘, NR. 0, S , Se, 00-R, %-R
The hindrance of rotation about the N-X bond is
often used as proof of the planarity of the nitrogen
atom. This is not evident because a partial double
bond character can also result from overlap of the
filled sp3 orbitals on nitrogen with the empty p orbital
on X. The nitrogen pyramid is flattened and the inversion rate on nitrogen increases by conjugation (see
section 3.4.1).
(32)
(33)
parable to the alkylated benzenes (15); the energy
threshold is higher because of the shorter bond (C-N
as compared with C-C)[41al. Examples from the
amides [ I l c l and nitrosamines [611 are (34)/(35) and
(36)/(37) respectively (the figures give AG? in kcall
mole).
The degree of steric hindrance in the transition state
of the rotation [(34) > (35); (36) > (37)] determines
the free enthalpy of activation AG:, which increases
with the bulk of the substituents; the same is true of
ring substitution [611.
1571 K . C. Ramey, D . C. Lini, and W. B. Wise, J. Amer. chem.
SOC.90, 4275 (1968), and literature cited therein; M . Tsutsui,
M . Hancock, J . Ariyoshi, and M . N . Levy, Angew. Chem. 81,
453 (1969); Angew. Chem. internat. Edit. 8, 410 (1969).
[ 5 8 ] V . R . Sandel, S . V . McKinley, and H . H . Freedman, J.
Amer. chem. SOC.90, 495 (1968); R . B. Bates, D . W. Gosselink,
and J . A . Kaczinski, Tetrahedron Letters 1967, 205.
[59] G . A. Oluh and J . M . Bollinger, J. Amer. chem. SOC.90,
6082 (1968).
[60] B. J . Price, J . A . Eggleston, and 1. 0 . Sutherlund, J . chem.
SOC.(London) B 1967, 922.
[61] A . Munnschreck and H . Muensch, Tetrahedron Letters
1968,
3227.
[62] T.H . Siddalland C . A. Prohasku, 3 . Amer. chem. SOC.88,
1172 (1966); Y . Shvo, E . C. Taylor, K . Mislow, and M . Ruban,
ibid. 86, 4910 (1967); T . H . SiddaN and W. E. Stewart, Chem.
Commun. 1968, 617.
[63] R . J . Seymour and R . C . Jones, Tetrahedron Letters 1967,
2021.
226
The temperature dependence of the nuclear resonance
has very often been used for the investigation of
rotation about the partial double bond in amides.
Since the discovery of the hindrance of rotation in dimethylformamide (39a) by Phillips 1641, the first application of the N M R method to the study of kinetic
processes, numerous articles dealing with the improvement of the measuring method and evaluation [2,13,15,231 as well as with the solvent and concentration dependence [2,22,651 of (39a) have been published. The substituents on the nitrogen and on the
carbon have also been varied and their effects on the
rate of rotation checked.
Let us first consider some examples that show the influence of the acy1,component (substituent R) on the
rotation barrier of N,N-dimethylamides (39) (Table 4).
The AGT values give a reliable indication at least of
the direction (accelerating or retarding) in which the
substituents affect the rotation rate.
The rotation about the amide bond (C-N) is hindered
by the participation of the limiting structure I in the
ground state. Pauling predicted an energy barrier of
[‘I This energy is comparable to that of a cis-trans isomerization about t h e amide bond. It is therefore possible that previous isomerization occurs into the trans form (35), in which the
rotation takes place more readily [ l l c ] .
[64] W. D . Phillips, J. chem. Physics 23, 1363 (1955).
[65] J . V . Hatton and W. G. Schneider, Canad. J. Chem. 40,
1285 (1962).
Angew. Chem. internut. Edit.
Vol. 9 (1970) / No. 3
about 21 kcal/mole, corresponding to a double bond
component of about 40 % [74J; this i s surprisingly close
to the value found experimentally for dimethyiformamide. Substituents influence the activation energy
I
H
J
(39)
both electronically and sterically [*I. A strong contribution of the limiting structure J to the resonance
reduces the double-bond character of the amide bond,
and hence also the rotation threshold. This effect is
clearly recognizable in the low A G z value of the
urethane (39g) as compared with those of the amides
(39a) and (396).
Table 4.
R
Hindered rotation in amides (391
Solvent
j
The bulkiness of the substitueqts can have various
effects:
1. Large substituents on the nitrogen and in the acyl
residue increase the energy content of the almost
planar ground state because of their steric interaction
(see also Section 3.4), with the result that the energy
difference for the transition state (A G i ) becomes
smaller. This probably explains why the rotation
barrier is lower for N , N-dimethyltrichloroacetamide
[(39d), AGZ m 15 kcal/mole] than for N,N-dimethyltrifluoroacetamide [(39e), AGZ w 18 kcal/mole]. A
similar effect is observed when the size of the residues
on the nitrogen is increased 1751.
2. Large substituents on the phenyl ring of benzamides
(39k), (391) lock the dialkylamino group, i.e. they
destabilize the transition state of the rotation, and so
give stable separable rotamers.
Replacement of the oxygen of the amide grouping by
other elements yields the compounds listed in Table 5.
The height of the rotation barrier, and hence the
double-bond character, decreases with variation of the
substituent Z in the order
Ref.
(kcal/mole)
I
without
without
without
without
without
without
CHCl3
without
Id1
[dl
[dl
21.7
18.9
16.7 [b]
14.9
17.6 [b]
16.8 [b]
14.8 [c]
16.1 [b]
14.4
22.5
% 30
116
87
61
14
95
53
- 13
e3
,NO2
O > N H z > C
S
,
N-Aryl > N-Alkyl
H
'
Electron-attracting substituents increase AG* (cf. [821).
A similar picture is found for N , N-dimethylbenzamide
12
168
>200
[a] For other alkyl groups, see [721.
[bl Based on 25 "C. [cl Calculated from the literature data.
[dl l-Chloronaphthalene/benzotrichloride (1 : 1).
[el Cf. also [73].
Table 5.
Cpd.
Z
Activation parameters for rotation in substances of the type (40).
Solvent
without
without
formamide
CDBr,
CDCI,
toluene
I
1
AGZ
(kcal/mole)
193
116
52
21.7 [a]
Ea
(kcal/mole)
log
27.9
20.5
19.6
13.6
12.7
12.7
Ref
16.5
14.1
11.9
[a] Based on 25 'C.
[b] Cf. also 1771.
Icl Cf. also [791.
[*I Too few data a r e available a t present for a quantitative
breakdown of the measured effects into t h e two contributions [66b].
[66] a) A . Mannschreck, Tetrahedron Letters 1965, 1341; b) R .
C. Neuman, Jr. and V. Jonas, J. Amer.chem.Soc. 90,1970 (1968).
1671 J . T. Woodbrey and M . T . Rogers, J . Amer. chem. SOC.84,
13 (1962).
[68] A . Allerhand and H . S. Gutowsky, J. chem. Physics 41,
2115 (1964).
[69] R . C. Neuman, J r . , D . N . Roark, and V. Jonas, J. Amer.
chem. SOC.89, 3412 (1967).
1701 E . Lusrig, W . R . Benson, and N . Duy, J. org. Chemistry 32,
851 (1967).
1711 H . A . Staab and D . Lauer, Chem. Ber. 101, 864 (1968)
1721 G . Isaksson and J . Sandstrom, Acta chem. scand. 21, 1605
(1967).
[73] B. J . Price, R . V . Smallman, and I . 0.Sutherland, Chem.
Commun. 1966, 319; H . Giinther and R . Wenzl, Tetrahedron
Letters I967, 4155; C. H . Bushweller and M . A . Tobias, ibid.
1968, 595; S. van der Werf and J . B. F. N . Engberts, ibid. 1968,
3311; C. E . Holloway and M. H . Gitlitz, Canad. J. Chem. 45,
2659 (1967).
Angew. Chem. internal. Edit. / Vol. 9 (1970)
No. 3
[74] L. Pauling: Die Natur d e r chemischen Bindung, 3rd Edit.,
Verlag Chemie, Weinheim/Bergstrasse, Germany 1968, p. 167.
[75] R . M . Hammaker and B. A . Gugler, J. molecular Spectroscopy 17, 356 (1965).
1761 A . Loewenstein, A . Melera, P . Rigny, and W . Walter, J .
physic. Chem. 68, 1597 (1964).
1771 G. S. Hanmond and R . C. Neuman, J r . , J. Amer. chem.
SOC.67, 1655 (1963).
[78] A . Mannschreck and U . Koelle, Tetrahedron Letters 1967,
863.
(791 H . E . A . Kramer and R . Gompper, Z. physik. Chem. 43,
292 (1964); M. Martin and G . Martin, C. R. hebd. Seances
Acad. Sci. 256,403 (1963); A . P . Downing, W . D . Ollis, and I . 0 .
Sutherland, Chem. Commun. I967, 143.
[SO] D . J . Bertelli and J . T . Gerig, Tetrahedron Letters 1967,
2481 ; J . P. Marsh and L . Goodman, ibid. I967, 863.
1811 D . L . Harris and K . M . Wellman, Tetrahedron Letters
1968, 5225.
1821 H . Kessler, Angew. Chem. 80, 971 (1968); Angew. Chem.
internat. Edit. 7, 898 (1968); Chem. Ber. 153, 973 (1970).
22 7
and its derivatives[841. In enamines (C<) and N-aryl
amidines (N-Aryl), the relationships are very strongly
dependent o n the substituents on the double bond and
on the aromatic ring. Thus a very much smaller AG*
value is to be expected for Z CH2 than for CHN02.
The rotation barriers are particularly high in thioamides [cf. (40), Z = S], so that some of these compounds can be resolved into rotational isomers [851.
This is due to the small tendency of sulfur to form
double bonds, which leads to a particularly large
contribution from the polar limiting structure [cf. I in
(39)]. The energy thresholds for rotation in thioamides, so far as this can still be detected by N M R
measurement, correlate well with the calculated xbond orders [831.
H’
R
-
tert-butylated compound [R == tert-C4Hg in (42)] is
the first N-monosubstituted amide for which both
rotamers have been isolated as such 1901.
Of the many articles on hindered rotation about
partial CN double bonds, we should like to draw the
reader’s attention to a few from the natural products
field 1911.
3.2.3. C a r b o n - O x y g e n a n d C a r b o n - S u l f u r
Single Bonds
Sterically hindered rotations about the C - 0 bond
have been detected in aromatic ethers and esters (43)
to (45) (see Table 6).
N-C:
R”
R
In N-monosubstituted amides (41), the rotamers have
different energy contents and participate unequally in
the thermal equilibrium. Numerous studies have been
carried out on compounds of this type, since they are
of particular interest in biochemistry (peptide linkage)[*6]. Both rotamers can always be detected in
formamides (R = H) 186,871, whereas in higher amides
(R = Alkyl) only the form (41a), in which the residues
R1 and R are trans to each other, are foundrssl. AGO
is usually greater than 2-3 kcal/mole; the concentration of the form (41b) is thus <5 %, and can n o longer
be measured (but cf. 1891).
In the ring-substituted acetanilides (42), on the other
hand, the Z form and the E formI89al have very similar
energies, and both can be detected[901. As in the (substituted) benzamides (3%) -(391) (Table 4), the energy
barrier for rotation increases with the bulk of R. The
~
(42)
_
_
[83] J . Sandstrdm, J. physic. Chem. 71, 2318 (1967).
[84] G . Schwenker and H. Rosswag, Tetrahedron Letters 1967,
4237; 1968, 2691.
[ 8 5 ] W . Walter and G . Maerten, Liebigs Ann. Chem. 715, 35
(1968); A. Mannschreck, Angew. Chem. 77, 1032 (1965); Angew. Chem. internat. Edit. 4 , 985 (1965); W . Walter, €. Schaumann, and K . J . Reubke, Angew. Chem. 80,448 (1968); Angew.
Chem. internat. Edit. 7, 467 (7968); W . Walter and G. Maerten,
Liebigs Ann. Chem. 669, 66 (1963).
[86] C. Franconi, Z . Elektrochem. 65, 645 (1961); L . A.
LaPIanche und M . T. Rogers, J. Amer. chem. S O C . 86,337 (1964).
[87] A . J . R . Bourn, D . G . Giliies, and E. W . Randall, Tetrahedron 22, 1825 (1966); H . Kessler, Angew. Chem. 80, 201
(1968); Angew. Chem. internat. Edit. 7 , 228 (1968).
[88] L. A . LaPIanche and M . T . Rogers, J. Amer. chem. SOC.85,
3728 (1963).
[89] R . H . Barker and G . J . Boudreaux, Spectrochim. Acta
23 A, 727 (1967).
[89a] J . E. Blackwood, C. L . Gladys, K . L . Loening, A . E.
Petrarea, and J . E. Rush, J. Amer. Chem. SOC.90, 509 (1968).
228
Jo2
Table 6 .
Sterically hindered rotation about the aryl-0 and aryl-S bond.
(43). R = OCsH5
(44)
(45)
146)
(47)
Ial
12.4
17.8
15.0
12.8
[a1
-30
54
12
-27
I921
1931
[94]
1941
[94, 9Sal
[a] Broadening in the spectrum at room temperature; n o data o n the
energy barrier.
[90] H . Kessler and A . Rieker, 2. Naturforsch. 226,456 (1967);
Liebigs Ann. Chem. 708, 57 (1967).
[9l] H. Paulsen and K . Todt, Chem. Ber. 100, 3397 (1967); W.
A. Szarek, S. W o r e , and J . K . N . Jones, Tetrahedron Letters
1964, 2743; R . J . Parry, Chem. Commun. 1967, 1294; R . R .
Shoup, H . T. Miles, and E. D. Becker, J. Amer. chem. SOC.89,
6200 (1967); D . M . G.Martin and C . 5. Reese, Chem. Commun.
1967, 1275.
1921 D. A . Bolon, J. Amer. chem. SOC.88, 3148 (1966).
[93] T . H. Siddall, W . E . Stewart, and M . L . Good, Canad. J.
Chem. 45, 1290 (1967).
[94] H . Kessler, A . Rieker, and W . Rundel, Chem. Commun.
1968, 475.
[95] a ) H . Kessler and W . Rundel, Chem. Ber. 101, 3350 (1968);
b) A . J . Gordon, private communication.
Angew. Chem. internat. Edit.
1 Vol. 9
(1970)
1 No. 3
The temperature dependence of the N M R spectra of
aromatic sulfides (46) and disulfides (47) must be
interpreted similarly. The hindered rotation about the
aryl-hetero aiom bond decreases with increasing size
of the hetero atom (O->S), as is shown by a comparison of the compounds ( 4 5 ) and (46).
This also gave a lower limit for the barrier for inversion
a t a dicoordinate oxygen atom. From the results of
measurements on (45), this barrier must be higher
than 17.8 kcal/mole in diary1 ethersr941. If we generalize
the findings for the inversion at nitrogen (Sections
3.3.2 and 3.4.1), the inversion barriers at the oxygen in
dialkyl ethers, alcohols, and water should be much
higher. This agrees with SCF calculations, which gave
a barrier of >34 kcal/mole for these compounds[95bl.
Table 7. Comparison of the -1C: and Tc values for rotations about
partial CN and N N double bonds.
AG?
(kcal/mole)
-~
21.7
23.3
-
3,172
17.0
11.8
15.9
15.7
Ref.
116
183
193
> 70(dec.)
49
- 39
* 17
35
;mag..
..
Z
\..
4
N-N
4
’ b - k
3.2.4. N i t r o g e n - N i t r o g e n a n d
Nitrogen-Oxygen Single Bonds
I
v
\.. P
Rotation
/N-N*
\..N-N=
$Z
Z
#
Inversion
The hindrance of rotation in nitrosamines (48) has
been known for some timer2,961. The high energy
threshold (>20 kcal/mole) separating the preferred
“planar” (cf. Section 3.2.2.2) conformations can be
explained by the strong contribution of the polar
limiting structure to the resonance. With suitable
substitution on the amino nitrogen, the rotamers are
so stable that they can be isolated as such 114,971.
Examples of other classes of compounds with hindered
rotation about the N-N bond are shown in Table 7.
The rotation barriers of similar N N and CN compounds are comparable in their order of magnitude.
Besides rotation, inversion consisting of folding in the
plane of the double bond is also conceivable at the
doubly bonded nitrogen atom in nitrogen compounds of the types (51)-(54).
A
However, an inversion of this nature is hindered by the
dialkylamino group (hetero effect, see Section 3.4)
and is therefore less likely.
The barrier for rotation about the dimethylamino
group in the substituted triazenes (55) has been correlated with the Hammett constant of X in the aryl
residue (p = -2.0 to -2.1) 1991. The difficulty of rotation
of the dimethylamino groups in the ketene aminals
(56) also increases with the ap constant (p =
-1.3) C82,112dl.
Like the types of compounds mentioned so far, the
alkyl nitrites (57) also exist as mixtures of cisoid and
transoid rotamers 121. The rotation barriers (approx.
10-14 kcal/mole) are lower than in the comparable
ni trosamines.
S
/O&N
Ye:.
H
H
H
R
fio
-
R\
4O
0-N
Suitable hydrazine derivatives give complex temperature-dependent N M R spectra [loo], which can
only be explained by assuming hindered rotation about
the NN single bond with simultaneous “slow” inversion at the nitrogen [loll. Calculations indicate that
the energy required for rotation about N N single
(54)
[961 R . K. Harris and R . A . Spragg, Chem. Commun. 1967,362.
I971 A . Mannschreck, H . Munsch, and A . Mattheus, Angew.
Chem. 78, 751 (1966).
Angew. Chem. internat. Edit.
Vol. 9 (1910) J No. 3
[98] W . J . Middleton, J. Amer. chem. SOC.88, 3842 (1966).
1991 M . H . Akhtar, R . S . McDaniel, M . Ferser, and A . C . Oehlschlager, Tetrahedron 24, 3899 (1968); N . P . Marullo, C. B.
Mayfield, and E . H . Wagener, J. Amer. chem SOC.90, 510
(1968).
[lo01 G . J . Bishop, B. J . Price, and I . 0 . Sutherland, Chem.
Commun. 1967,612; B. H . Korsch and N . V . Riggs,Tetrahedron
Letters 1966, 5891.
[loll J . E . Anderson and J . M . Lehn, Tetrahedron 24, 123
(1968).
229
bonds (ca. 12 kcal/mole [1021) is significantly greater
than for rotation about CC single bonds (approx.
3 kcal/mole).
3.2.5. R o t a t i o n A b o u t O t h e r S i n g l e B o n d s
Hindrance of rotation about S-S and Se-Se bonds
has been found in sterically hindered aromatic disulfides and diselenides (58) 1951.
is weakened, as in compounds of the types
and (62) [1071.
In the calicene derivatives (61), strong participation
of the polar limiting structure is to be expected. This
greatly reduces the double-bond character and lowers
the rotation barrier (cf. [log]). A polar limiting structure is also conceivable in (62), though less likely. The
The rotation about the P-N bond in (59) can be
"frozen in"t1031. The rotation barriers are lower in
these compounds than in the hydrazine derivatives,
since the greater distance between P and N leads to a
decrease in hindrance. The repulsion of the lone pairs
of electrons is undoubtedly partly responsible for the
magnitude of the hindrance of rotation about
N-O [1@3bI,N-N, N-S [1@47,and N-P bonds.
The trimesityl compounds of the elements of Group
V [(6Oa)-(6Od); the values in parentheses are AGZ
(kcal/mole) and Tc ("C)] are comparable to the triarylmethane derivatives (14). The hindrance of
rotation about the aryl-Z bond decreases as the size of
the atom Z increases [341. The observed temperature
dependence of the N M R spectra is therefore not due
to inversion at the Z atom (see Section 3.4).
"
I
(59)
(58). Z = S, S e
CH3
CH3+Z\RTI
-
cH3
( 6 0 ~Z
) =
(60b) Z =
( 6 0 ~ )Z =
(60d) Z =
(61)[1061
R
$
R
c)
R
(61)
(62)
R
R
f 63 b)
0 (63a)
R
= tert.-C,H,
investigation of suitable p-diphenoquinones (63a) [lo91
and quinonemethides (63b) [1101 shows in fact that the
symmetry plays an important part. Neither electronattracting nor electron-repelling residues R1 in quinonemethides (636) are sufficient to lower the rotation
barrier to such a degree that it can be determined by
N M R spectroscopy. The rotation is sufficiently fast
only in the symmetrical quinonemethide (64b),
whereas the barrier in the electronically comparable
but unsymmetrical quinonemethide (64a) is considerably higherrllol (the figures indicate AG* in kcal/
mole).
P(12.4; - 3 5 )
As (9.3; -91)
Sb ( G . 3 ; <-120)
B i (<7.3; <-120)
R' = M e s i t y l
(60)
R
R
R = tert. -C,H,
>25.6
R = tert.-C,H,
(644
(64 b)
3.3. Isomerizations at Double Bonds
19.9
3.3.1. C a r b o n - C a r b o n D o u b l e B o n d
The C C double bond has a very high configurational
stability[*]. The rotation becomes detectable in the
N M R spectrum only when the double-bond character
[lo21 A . Veillard, Theoret. chim. Acta 5 , 413 (1966).
[103] a) D . Imbery and H . Friebolin, Z . Naturforsch. 23b, 759
(1968); A . H . Cowley, M . J . S . Dewar, and W . R . Jackson, J.
Amer. chem. SOC.90, 4185 (1968); b) M . Raban and G . W .
Kenney, Tetrahedron Letters 1969, 1295.
[lo41 J . M . Lehn and J . Wagner, Chem. Commun. 1968, 1298;
M . Raban, F. B. Jones, and G. W. J . Kenney, Tetrahedron Letters 1968, 5055; M . Raban, G. W . Kenney, and F. R. Jones, J.
Amer. chem. SOC.91, 6677 (1969).
[ * ] T h e cis-trans isomerization in 1,2-dideuteroethylene requires 65 kcal/mole. It may proceed via the triplet or theexcited
singlet state; the latter possibility is more likely [IOS].
[I051 M . C . Lin and K . J . Laidler, Canad. J. Chem. 46, 973
(1968); J . E . Douglas, B. S. Rabinovitch, and F. S. Looney, J.
chem. Physics 23, 315 (1955).
230
This observation points to uncoupling of the x electrons in the transition state (65). This cannot be the
triplet state of the olefin because for the singlet-triplettransition one would except a low transmission coefficient in the Eyring equation and also a low fre[I061 A . S . Kende, P . T . Izzo, and W. Fuimor, Tetrahedron
Letters 1966, 3697.
[lo71 H. Kessler and A . Rieker, Tetrahedron Letters 1966,5257.
[lo81 J . H . Crabtree and D . J . Bertelli, J. Amer. chem. SOC. 89,
5384 (1967); G. Seitz, Tetrahedron Letters 1968, 2305.
[lo91 A . Rieker and H. Kessler, Chem. Ber. 102, 2147 (1969);
P . Boldt, private communication.
[llO] A . Rieker and H . Kessler, Tetrahedron 24, 5133 (1968).
Angew. Chem. internat. Edit.
/ Vol. 9
(1970)
1 No. 3
quency factor A in the Arrhenius equation. The normal log A value (11.4) found for (63a) [I091 gives evidence for the singlet biradical transition state of the
rotation in these cases. The ease of rotation in hexapentaene can probably by explained in a similar
manner 11111.
It can be seen from the gradient of the log k / a correlation lines that the rotations about both C N single
bonds and about the C-aryl bond are hindered by
electron-attracting substituents, while the rotation
about the central CC double bond is greatly facilitated.
3.3.2. C a r b o n - N i t r o g e n D o u b l e B o n d
Rotation a n d Inversion
There are in principle two possibilities for the synanti isomerization in imines (69) (cf. Section 3.2.4).
Substituents X and 2 in (66) and (67) with strongly
electron-repelling or electron-attracting effectsr1121
weaken the double bond sufficiently for the rotation
to be measured by NMR spectroscopy. SR, OR, and
NR2 have been investigated as electron-repelling substituents, and NOz, CN, COR, COOR, and aryl as
electron-attracting substituents[82,112]. Up to four
rotations can be detected simultaneously in 2-aryl-2cyano-1 ,I-bis(dimethy1amino)ethylenes (68) [82,112dl. A
different coalescence temperature is found for each
iotation.
The kinetic data found from the spectra for all four
rotations can be correlated with the Hammett 0 constants of the residues R in the benzene ring (Fig. 7).
121-
a) Rotation. The substituent Z describes a circle about
the axis of the C-N bond (“out of plane” isomerization, K). The process is favored by polarization of the
C N double bond. The sp2 hybridization of the nitrogen atom, and hence the bond angle (C-N-Z), is
retained.
x,CO,x
x\c’x
a h - w
X
@
.
II
N
EJ:N-
dKZ
“Z
Q?
(69)
K
b) Inversion. The N-Z bond swings in the bond plane
of the imine system from the syn into the (identical)
anti position (“in plane” isomerization, L). The bond
angle (C-N-Z) increases to 180 in the transition
state. The C N double bond is, to a first approximation,
unaffected.
(70)
L
The influence of p substituents R in the aryl residue of
N-arylimines of the type (71) on the free enthalpy of
activation of the syn-anti isomerization follows the
Hammett relation [113-1161. Contrary t o previous
reports in the literature[1231 we were also able to show
such a correlation in imino esters[*]. Irrespective of the
substituent X, the reaction constant is p = 1.7 [1163. A
substituent R in benzylideneamines (72), on the other
hand, has a much smaller influence (p = -0.4)[1171.
The difference in the effects of variation of substituents
on the N and on the C atom has been taken as evidence of inversion [1131.
(72)
Fig. 7. H a m m e t t correlation of th e rotations in ketene aminals (68).
111 l ] R. Kuhn, B. Schulz, and J . C. Jochiins, Angew. Chem. 78,
449 (1966); Angew. Chem. internat. Edit. 5 , 420 (1966).
[112] a ) G. Isaksson, J . Sandstrom, and 1. Wennerbeck, Tetrahedron Letters 1967, 2233; b) Y . Shvo, €. C. Taylor, and J . Bartulin, Tetrahedron Letters 1967, 3259; Y . Shvo, ibid. 1968, 5939;
C) A . P . Downing, W . D. Ollis, and I . 0 . Sutherland, J. chem.
S O C . (London), B 1969, 111 and literature cited therein; d) H .
Kessler, Chem. Ber. 103, 973 (1970).
Angew. Chem. internat. Edit.
Vol. 9 (1970)
No. 3
I1131 D . Y . Curtin, E . J . Grubbs, and C. G McCarty, J. Amer.
chem. SOC. 88, 2775 (1966).
[114] A . Rieker and H . Kessler, Tetrahedron 23, 3723 (1967).
11151 H . Kessler, Tetrahedron Letters 1968, 2041.
L*] H . Kessler, and D . Leibfritz, unpublished.
[1161 a ) H . Kessler and D. Leibfritz, Tetrahedron, in press;
b) ibid. 25, 5127 (1969).
11 171 G . Wettermark, J . Weinstein, J . Sousa, and L . Dogliotti,
J . physic. Chem. 6 9 , 1584 (1965).
23 1
The small influence of the polarity of the solvent on
the rate of isomerization of tetramethylphenylguanidine points to a similar conclusion [115,116bl. A polar
solvent should facilitate isomerization by rotation, as
has been found e.g. for ketene aminals [112dl.
The influence of residues R in the o-position in arylimines (73) is particularly impressive. The activation
threshold is lowered as the size of R increasescl16.
118-1201. This can only be explained by inversion, in
version at tricoordinate nitrogen (e.g. in aziridines,
see Section 3.4.1.1) 11161. The isomerization rate increases very rapidly as the substituent Z is varied in
the order:
RO
(73)
which the steric hindrance is less in the extended
transition state than in the ground state. Rotation
would be hindered by the substituents R. Figure 8
shows a comparison of the AG: values for the
inversion in guanidines (74)[1161 with those for rotation
about the CN double bond in the guanidinium salts
(75) [1211 [*I, in which the lone pair of electrons is
fixed and inversion is consequently impossible.
f 75)
f 74)
= R2N < halogen < alkyl < aryl < acyl
Substituents X on the imino carbon atom also increase the inversion rate, the order being 1115,116aI:
quinone ring
< alkyl < acetyl < alkoxycarbonyl < aryl <
methoxy 1123, 1241 < alkylthio [124] < dialkylamino
With the aid of these sequences, it is possible to
predict the rate constants within wide limits.
The fast inversion at nitrogen also explains why carbodiimides (76), unlike allenes, do not form stable isomers. As predicted from calculations r1251, the diastereotopic geminal H and CH3 groups in the residues
R have been found to be NMR-spectroscopically
equivalent even at -100°C. The activation energy of
the inversion is presumably smaller than m9 kcal/
mole in these compounds [451.
R = C2H5, i-C,H,,
CH2C6H5
3.3.3. I s o m e r i z a t i o n a t O t h e r D o u b l e B o n d s
Isomerizations of oxonium and sulfonium salts containing CO and CS double bonds, e.g. (77), are closely
related to the isomerizations just described.
Fig. 8. Free enthalpies of activation for inversion [guanidines (7411
and rotation [guanidiniurn salts (75)J at doubly bonded nitrogen atoms.
The contrary substituent effects in the two series and
the low energy barriers for the syn-anti isomerization
of the guanidines (74) also indicate that the process
involved is an inversion.
Another argument in favor of inversion is the similarity of the effect of the substituent Z on the syn-anti
isomerization in imines (X2C=NZ) and on the in-
In the protonated carbonyl compounds [(77), Z = HI
that have been the subjects of most of the investigations [**I, isomerization by deprotonation/reprotonation is possible as well as the rotations and inversions
discussed for the CN double bonds 1126bl. Experiments with systematic variation of the substituents,
which should make it possible to decide which course
is in fact followed, have not yet been carried out.
In the series of sulfur compounds, investigations have
been carried out on the thiuronium salts (78) [1211.
The influence of the substituent Z on the isomerization
rate in these compounds is comparable to that in
Ill81 A . Rieker and H . Kessler, Z . Naturforsch. 21b, 939 (1966).
11191 H . Kessler, Angew. Chem. 79,997 (1967); Angew. Chem.
internat. Edit. 6, 977 (1967).
[120] D . Wurmb-Gerlich, F. Vogtle, A . Mannschreck, and H . A .
Staab, Liebigs Ann. Chem. 708, 36 (1967).
[121] H . Kessler and D . Leibfritz, Tetrahedron Letters 1969,
11231 N . P . Marullo and E . H . Wagener, J. Amer. chem. SOC.
88, 5034 (1966).
[124] F. Vogtle, A . Mannschreck, and H . A . Staab, Liebigs
Ann. Chem. 708, 51 (1967).
11251 M . S. Gordon and H . Fischer, J. Amer. chem. SOC. 90,
2471 (1968); J . M . Lehn and B. Munscli, Theoret. chim. Acta 12,
427.
[*] Rotation about the CN double bond has also been ob-
91
served in a nitrone [122].
[122] R . W. Layer and C. J . Carman, Tetrahedron Letters 1968,
1285.
taken into account.
11261 a ) D . M . Brouwer, Recueil Trav. chim. Pays-Bas 86, 879
(1967); b) H . Hogeveen, ibid. 86, 696 (1967).
23 2
(1968).
[**I I n the literature the possibility of inversion is not usually
Angew. Chem. internat. Edit.
1 Vol. 9
(1970)
1 NO. 3
state by a change in the hybridization of the nitrogen
atom from sp3 to sp2f*].
(77)
2 = H ; X = alkyl 11261, aryl [127], OH [128], alkoxy [I291
Z = alkyl; X = alkyl, alkoxy [130], H 11311, p-quinonoid
ring [132]
Z = aryl; X = dialkylamino, alkoxy, alkylthio [132a]
The barrier in ammonia and in many amines is so low
( $ 6 kcal/mole) that it is difficult to detect by N M R
spectroscopy, though the inversion rates can still be
determined in such cases from the p H dependence of
the spectra 11351. With suitable substituents, however,
the pyramidal arrangement can be stabilized sufficiently to allow even the separation of invertomers
(AG* > 23 kcal/mole).
3.4.1.1. I n f l u e n c e of R i n g S t r a i n
(78)
guanidinium salts (75) (451. Thus large residues in the
o-positions of S-arylthiuronium salts hinder the process, indicating that rotation is involved.
The inversion barrier is much higher in the azetidines
(81) and aziridines (82)-(84) than in the unstrained
pyrrolidines (80). (AG* is given in kcal/mole under
the formulas).
The inversion seems to have been conclusively verified
in the imines. Some sulfonium salts appear to isonierize by rotation, but it is still too early to generalize.
Inversion is more likely in oxonium salts than in the
sulfur analogs. However, no investigations on this
point have been carried out as yet.
nversion
-
Rotation
1nversion['331
Rotation is the only possibility for cis/truns isomerization in olefins and immonium salts, apart from the
protonated imines, in which inversion by deprotonation/reprotonation is also conceivable.
3.4. Inversions
3.4.1. I n v e r s i o n a t t h e N i t r o g e n A t o m
The inversion of the nitrogen pyramid in amines has
been known for a long time. It proceeds via a planar
[127] R. van der Linde, J . W. Dornseffen, J . 0. Veenland, and
T . J . de Boer, Tetrahedron Letters 1968, 525.
I1281 H . Hogeveen, A . F. Bickel, C . W. Hilbers, E . L . Mackor,
and C . McLean, Recueil Trav. chim. Pays-Bas 86,687 (1967).
1129) G. A . Oiah and A . M . White, J. Amer. chem. SOC.90,
1884 (1968).
[130] B . G. Ramsey and R . W . Taft, J. Amer. chem. SOC.88,
3058 (1966).
11311 R . F. Borch, J. Amer. chem. SOC.90, 5303 (1968).
I1321 D . M . Brouwer, E. L . Mackor, and C. McLean, Recueil
Trav. chim. Pays-Bas 85, 114 (1966).
[132a] H . Kessler and H . 0 . Kalinowski, unpublished.
(1331 E . R . Talatv and J . C. Fargo, Chem. Commun. 1967, 65;
1. G. Murgulesen and 2. Simon, Rev. Roumaine Chim. 11, 21
(1966).
Angew. Chem. internat. Edit. J Vol. 9 (1970)
1 No. 3
An intuitive explanation of this phenomenon can be
obtained by considering the transition state. In the
planar state, the nitrogen is sp2-hybridized, so that the
bond angle must increase to 120 "C during the inversion. When the nitrogen is incorporated in a small ring,
however, the necessary spreading is hindered, i.e. the
activation energy increases.
On the other hand, the s-character of the lone electron
pair on nitrogen is much higher in the three-membered
ring than in acyclic amines. This is indicative of a
ground state stabilization with respect to the inversion
transition state.
._.__
[*I With H atoms on the nitrogen, inversion is also possible by
the tunnel effect 11341. This process becomes increasingly unlikely as the mass of the substituents o n t h e nitrogen increases.
[l34] H . A. Stuart: Molekiilstruktur, Springer-Verlag, Berlin
1967, p. 475.
[I351 J . J . Delpueck and M . N . Deschamps, Chern. Commun.
1967,1188; J . L . Sudmeier and G . Occupati, 3. Amer. chem. SOC.
90, 154 (1968).
[136] a ) J . B. Lambert and W . L. Oliver, J. Amer. chem. SOC.
91,7774 (1969); b) J . M . Lehn and J . Wagner, Chem. Commun. 1968, 148.
[137] A . Loewenstein, J . F. Neumer, and J . D . Roberts, J. Amer.
chem. SOC. 82, 3599 (1960).
[138] A . T. Botrini and J . D. Roberts, J. Amer. chern. SOC.80,
5203 (1968).
[1391 S . J . Brois, J. Amer. chem. SOC.89, 4242 (1967).
233
3.4.1.2. S t e r i c E f f e c t
The AG+ value decreases with increasing size of the
residues on the nitrogen [cf. the series (82)-(83)-t
(84)l. This effect, which is not very large, is due to the
fact that the steric hindrance is less in the planar
transition state than in the pyramidal ground state.
3.4.1.3. E l e c t r o n i c E f f e c t s
Electron-attracting substituents strongly depress the
inversion barrier [cf. the series (82) +(85) +(86) --f
(87), with indicated AG* values].
The inversion in systems of this type is easy to follow
by N M R spectroscopy. The inversions of the two N
atoms do not occur simultaneously ‘1451.
The hetero effect, which is also found in imines (cf.
Section 3.3.2), could have two causes. 1. As the electronegativity of the substituents increases, so also does
the s character of the lone pair of electrons on the
nitrogen[146J, with the result that the energy difference
for the transition state (p character of the lone pair of
electrons) increases. 2. The transition state is destabilized by the mutual repulsion of the lone pairs of electrons onthe nitrogenand on the heteroatom. It is not yet
possible to say which of these two effects predominates.
T h e configuration-stabilizing effect of halogen a t o m s shows
t h a t (p-d)r interaction cannot play any decisive part in t h e
transition state. Sulfur substituents, on the other hand, appear to accelerate t h e inversion r1041. T h i s is contrary to
findings in s o m e earlier investigations, in which a “slow”
inversion is assumed for sulfenamines “471. However, t h e temperature effect observed in these investigations can be better
explained by hindered rotation a b o u t t h e SN bond.
Appreciable stabilities of the nitrogen pyramid are
achieved by combination of the ,effects of ring strain
and of hetero substitution.
8
This effect, which stabilizes the planar transition state,
is also the reason for the very fast nitrogen inversion in
amides, which cannot be detected by N M R spectroscopy.
Electronegative substituents Z (halogen, oxygen,
nitrogen) stabilize the pyramidal ground state of the
nitrogen atom (“hetero effect”). Thus the inversion
barrier has been measured in hydroxylamines 1103,142bl
and hydrazine derivatives [loo, 1431 by NMR spectroscopy, though the inversion is to fast for measurement
in this way in other acyclic amines.
Many articles have appeared on compounds (88), in
which two nitrogen atoms are built into adjacent
positions in ring systems [144,1451.
R = Alkyl, Acyl, C a r b o x y l , (CH,),
etc.
11401 F. A . L . Anet, R . D . Trepka, and D . J . Cram, J. Amer.
chem. SOC.88, 357 (1967).
[141] F. A . L . Anet and J. M . Osyany, J. Amer. chem. SOC.89,
2072 (1967).
[I421 D . L. Griffith and 1. D . Roberts, J. Amer. chem. S O C . 87,
4089 (1965); B. J. Price and I . 0. Sutherland, Chem. Commun.
1967, 1070; D. L . GrSffith and B . L . Olson, ibid. 1969, 1682; F.
G. Riddell, J . M . Lehn, and J . Wagner, ibid. 1968, 1403.
[143] R. M . Moriarty, sen., M . R . Murphy, S . J. Druck, and L.
May, Tetrahedron Letters 1967, 1603.
[144] E. L . Allred, C . L . Anderson, R . L . Miller, and A . L . Johnson, Tetrahedron Letters 1967, 525; E . Fahr, W . Fischer, A .
Jung, L. Sauer, and A . Mantischreck, ibid. 1967, 161; B. Junge
and H . A . Siaab, ibid. 1967, 709; J . Wagner, W. Nojnaroivski,
J . E. Anderson, and J. M. Lehn, Tetrahedron 25,657 (1969), and
literature cited therein; J . M . Lehn and J . Wagner, ibid. 25, 677
(1969).
[145] J . E. Anderson and J . M . Lehn, J. Amer. chem. SOC. 89,
81 (1967).
234
Stable nitrogen invertomers were first separated by
Felix and Eschenmoser and by Brois in the halogenoaziridine series ( 8 9 ~11481.
)
Invertomeric oxaziridines
[(90a), Z -- 0][15oal and diaziridines [(906), Z =
NR]Il5obl are also stable at room temperature.
If the nitrogen atom is substituted with two hetero
atoms, the pyramid is stable to inversion even in rings
with more than three members. This was recently
demonstrated in the case of an N-methoxy-l,2-oxazolidine 11511.
Hindrance of the inversion by steric effects has been
observed in dihydroquinolone systems (91) [1521.
(1461 H . A . Bent, Chem. Reviews 61, 275 (1961).
12471 K. Murayama and T . Yoshioka, Tetrahedron Letters 1968,
1363; M . Raban, G. W . J . Kenney, J . M.Moldowan, and F. B.
Jones, J. Amer. chem. SOC.90,2985 (1968); H . J. Jakobson and
A . Senning, Chem. Commun. 1967, 617; M . Raban, Chem.
Commun. 1967, 1017.
[148] S. J . Brois, J. Amer. chem. SOC.90, 506, 508 (1968); D .
Felix and A . Eschenmoser, Angew. Chem. 80, 197 (1968); Angew. Chem. internat. Edit. 7 , 224 (1968); R . G. Kosryatzovsky,
2.E. Samojlova, and J .J.Tchervin,Tetrahedron Letters 1969,719.
[149] R . S. Aikinson, Chem. Commun. 1968, 676; S. J . Brois,
Tetrahedron Letters 1968, 5997.
[150] a ) F. Montanari, I . Moretfi, and G. Torre, Chem. Commun. 1968, 1694; D . R . Boyd, Tetrahedron Letters 1968, 4561;
A . Mannschreck, J . Linss, and W. S e if z , Liebigs Ann. Chem.
727, 224 (1969); b) A . Mannschreck, R. Radeglia, E. Griindermann, and R . Ohme, Chem. Ber. 100, 1778 (1967); A. Mannschreck and W. Seitz, Angew. Chem. 81, 224 (1969); Angew.
Chem. internat. Edit. 8, 212 (1969).
[151] K. Muller and A . Eschenmoser, Helv. chim. Acta 52, 1823
(1 969).
11521 W . N . Speckamp, U.K . Pundit, P . K . Korver, P . J . van der
Haak, and H. 0 . Huismann, Tetrahedron 22,2413 (1966).
Angew. Chem. internat. Edit. / Vol. 9 (1970) / No. 3
3.4.2. O t h e r I n v e r s i o n s
Inversions can also occur at other atomsL152,1531.
EG
'/
'
/,.,
..
The pyramids of carbanions (92) and oxonium salts
(94) are isosteric with those of amines (93). The inverting central atoms can also be replaced by other elements from the same group of the periodic system.
The number of possible inversions is considerably
increased by the inversion processes in the systems
(95) to (97) containing doubly bonded atoms. N M R
studies have so far been carried out on only a few inversions at atoms other than nitrogen [*].
Thus Anet et al. studied the inversion in cyclic carbanions (98) [*551, and Lambert et al. analysed the same
process in the oxonium salts (99) 11561 (the figures are
the AG* values for inversion in kcal/mole).
17-18 (98)
-10 199)
(100)
Z = P, A s
Surprisingly low values of 26 kcal/mole were found
for the inversion barriers for phosphorus and arsenic
in compounds (100) (1571. The inversion of Grignard
compounds has also been investigated 11581. Organo(1531 G. W . Koeppl, D . S . Sagatys, G. S. Krishnamurthy, and
S . I . Miller, J. Amer. chem. SOC.89, 3396 (1967).
[ * ] In this connection, mention should be made of the pseudorotation a t pentacoordinate phosphorus (1541. This process
involves a rearrangement of the ligands that requires a change
in t h e hybridization of the central atom in t h e transition state.
Inversions a t bivalent atoms fe.g. a t oxygen in ethers, alcohols,
and water) with linear transition states a r e briefly discussed in
Section 3.2.3 for interconversions of C~ 0 bond rotamers.
[154] G. M . Whitesides and W . M . Bunting, J. Amer. chem. SOC.
89, 6802 (1967); D . Hellwinkel, Angew. Chem. 78, 749 (1966);
Angew. Chem. internat. Edit. 5 , 725 (1966).
[155] A . Ratajczak, F. A . L . Anet, and D . J . C r a m , J. Amer.
chem. SOC.89, 2072 (1967).
[156] J . B. Larnbert and D . H . Johnson, J. Amer. chem. SOC. 90,
1349 (1968).
I1571 J . B. Larnbert, G. F. Jackson 111, and D . C . Mueller, J .
Arner. chem. SOC.YO, 6401 (1968).
ll581 G. Fraenkel, D . T . D i x , and M . Carlson, Tetrahedron
Letters 1968, 579, and literature cited therein.
Angew. Chem. internat.
Edit. 1 Vol. 9 (1970) / No. 3
metallic compounds of the type (92) usually exhibit
complete racemization in chemical reactions [2*1.
Stereospecific reactions are possible only when the
inversion barrier is increased by ring strain, as in the
aziridines t7-81. The inversion therefore becomes increasingly easy in the order (92)+(93) +(94). If this
observation is generalized, one should expect very
small inversion barriers ( ( 5 kcal/mole) in acyclic
oxonium salts of the type (94).
Similar results can be deduced for the species (95)-.
(96) +(97). Whereas vinyllithium compounds of the
type (95) ieact stereospecifically (or stereoselectively)[28J, the inversion rates for imines lie in the NMR
measurement range, and the ketonium salts (97)
appear from preliminary results I451 to invert faster
than comparable imines.
In species with the same central atom [e.g. (92) and
(95) or (93) and (96J1, types (95) and (96) have a
distinctly higher barrier than types (92) and (93).
These cautious generalizations require further experimental confirmation.
The inversions of comparable pyramidal compounds
should also become increasingly difficult with decreasing electronegativity of the central atom, i.e. in the
order e.g. N-+P+As, since the s character of the lone
pair of electrons increases in this order [1461, and the
stronger the s character in the ground state, the more
difficult is the inversion via a state in which the lone
pair of electrons has pure p character.
Care is necessary in the interpretation of inversion
barriers, since the mirror-image invertomer can be
formed not only by direct intramolecular inversion
but also by dissociation and recombination of the
fragments. Isomerization by rotation must also be
considered in the case of doubly bonded atoms (see
Section 3.3.2).
N M R spectroscopy is a good method for the study of
the substituent effects and the influence of the central
atom on the inversion rates. The current interest in
this topic is obvious from the number of publications
that have appeared in recent years.
The investigations by our research group that are mentioned here were carried out with the support of the
Deutsche Forschungsgemeinschaft, for which I am
grateful. I also thank Prof. Dr. Eugen Miiller for his
interest in the work. Thanks are also due to Doz. Dr.
A . Rieker for perusal of the manuscript and for numerous discussions, as well as to Dip1.-Chem. D . Leibjritz
and Fraulein C . Burk for their assistance.
Received. March 28, 1969
[A 748 1El
German version' Angew. Chem. 82, 237 (1970)
Translated by Express Translation Service, London
235
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