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Heterocyclic Systems Having Eight -Electrons.

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Volume 14. Number 9
September 1975
Pages 581- 654
International Edition in English
Heterocyclic Systems Having Eight x-Electrons. Synthesis, Properties,
and Significancer1]
By Richard R. Schmidt [*I
The terms “aromatic” and “antiaromatic” have attracted widespread interest in recent years.
After all the discussion about the meaning of words, one fact remains: the energy content
of planar systems displaying cyclic electron delocalization depends upon the number of, and
the orbital interactions between, the participating electrons. The concept underlying this progress
report is that the electronic destabilization of systems having eight x-electrons should be
especially pronounced in the case of six-membered rings for steric and electronic reasons.
Such systems are found primarily in anionic, but also in neutral, heterocycles containing
hetero ring members which possess electron pairs capable of delocalizing into the x-system.
The production and reactivity of such systems are investigated and their biological significance
1. Introduction
have a higher energy content than comparable open-chain
systems. B r e s l ~ w [ and
~ ’ D e w ~ r [therefore
propose the use
1.1. Aromatic and Antiaromatic Systems
Recent theoretical concepts teach that the number and orbital interaction of cyclically delocalized electrons are of considerable significance for the stability of molecular ground states
and the energy content of transition states. The Huckel rule
and the Woodward-Hoffmann rules, confirmed by numerous
experimental examples, provide impressive support for these
Thus calculations of the resonance energy per n-electron
for annulenes and IH-I-azaannulenes (see Fig. I), relative
to the corresponding acyclic conjugated planar systems, reveal:
(4n + 2)n-systems are stabilized by resonance and the corresponding 4mr-systems, with which this report is concerned,
are destabilized’*’.
Studies on cy~lobutadiene~~]
and on cyclopropenyl
anions’“ 51 (4n-systems) show that these systems do indeed
= -a12
-0 18
--- -
[*] Prof. Dr. R. R. Schmidt
lnstitut fir Organische Chemie, Biochemie und Isotopenforschung der
7 Stuttgart 80, Pfaffenwaldring 55 (Germany)
Angew. Chrm. internat. Edit.
/ Yo/. 14
/ No. 9
Fig. I . Resonance energy per x-electron (REPE) for annulenes (--)
1H-1-azaannulenes (---). n =number of ring members [2].
of the terms "aromatic" and "antiaromatic" in characterizing
this phenomenon of alternating energy content in formally
related systems, and classification of the corresponding acyclic
reference system as "nonaromatic". Thus defined, these terms
provide a qualitative description of an important ordering
principle in the chemistry of cyclically conjugated systems
and are of theoretical and practical utility. Since a clear-cut
answer to the important question of the reference system
is not always available, a formalistic and noncritical usage
of the terms "aromatic" and "antiaromatic" has repeatedly
aroused opposition['- 'I.
potential 8rc-systems-systems of considerable significance in
the biological sector. Furthermore, a brief account of sevenmembered anionic systems will also be presented.
1.2. 8nSystems in Heterocycles
The agreement observed between calculation and experimental results in the case of cyclobutadiene no longer exists
on going to cyclooctatetraene ( I ) : typically olefinic character
is found['01.The reason lies in the molecular geometry. An
important prerequisite for electron delocalization is not satisfied, i. e. planarity of the molecular skeleton. rc-Conjugation
of the cyclic 8rc-system, and hence electron delocalization,
is thwarted by the angular skeleton. The dihedral angle
between the rc-bonding planes is about 90'[' ' I ; localized rcbonds are present.
Replacement of an ethylene group of cyclooctatetraene ( 1 )
by a hetero atom bearing a free electron pair leads to the
seven-membered heterotropilidenes (hetero-n-homobenzenes)
(2), which are likewise potential 8n-electron systems[I2*1 3 ]
with antiaromatic character (see Fig. 1). Nor are these systems
planar['4! The more or less pronounced valence isomerization
to the hetero-o-homobenzenes (3) has at least three reasons:
a) steric reasons-nonplanarity leads to spatial proximity of
the atoms forming the new x-bond; b) differing strength of
the new o-bond-this
phenomenon can be rationalized
according to Hoffrn~nn['~]
and Giinther['61with the aid of
the Walsh MO model, thus leading to the prediction that
the new o-bond will be the stronger the more electronegative
the hetero atom happens to be; c) the hitherto little-discussed
electronic destabilization of the 8rc-system[' 2, "I. This destabilization becomes clearly apparent on comparison of the heterosystem with cyclooctatetraene and cycloheptatriene; it is seen
as an enhanced reactivity which manifests itself in valence
isomerizations, rearrangements, and additions[". I3l.
Replacement of two ethylene groups in cyclooctatetraene,
each by a hetero atom having a free electron pair, will yield
the six-membered potential 8n-systems ( 4 ) and ( 5 ) , which
should be essentially planar with bond angles of about I 2 0
According to MO calculations['*.
these are particularly
favorable models displaying electronic destabilization. Compounds of this type do indeed show remarkable behavior
in their reactions['- 2ol.
Even more reactive potential cyclic 8n-systems should arise
on replacement of X or Y in ( 4 ) or ( 5 ) by a carbanion
center, as in ( 7 ) and ( 9 ) ; their tendency to stabilize the
negative charge raises the electronic destabilization. Such systems are accessible by deprotonation of suitable dihydroheterocycles like (6) or (8)r',201.
The significance of the heterotropilidenes such as (2) has
been underlined above all by the work of Vogel, Hafner, Prinzh u h , and their respective co-workersrl2.' I. This progress
report will be concerned in particular with the generation
and properties of six-membered anionic and also neutral
a, b, c, d = C - R , N, e t c .
X, Y = 0, S, N-R, e t c .
2. Six-Membered Heterocyclic Systems with Eight nElectrons
2.1. Systems Analogous to Oxepin
2.1.1. 1,3-Oxazinyl Anions
Our work on six-membered anionic 8rc-systems began with
, which are readily
the study of 4H-1,3-oxazines ( 1 0 ) [ 2 1221,
accessible by polar c y ~ l o a d d i t i o n [241.
~ ~ .Reaction of ( l o ) ,
R'=R2=aryl, with strong bases at low temperatures (up to
H R2
Scheme I
[*] Anionic systems having eight delocdlizable il-electrons will be depicted
in this manncr.
Ariym.. Clierri. I I I I C ~ I I U ~ E. d i ! .
' KJI. 1 4 ( 1 9 7 5 )
I Nu. 9
-120°C) in T H F yields a dark blue solution. This color
is attributed to the 1,3-oxazinyl anion ( I I ) (Scheme 1). HOWever, the rapid disappearance of the color suggests (11) to
contain so much energy that it rapidly transforms into a
ring-strained, valence-isomeric bicyclic compound, even at
- 120°C.
The oxazinyl anion (1 I ) possesses ambivalent character
and can undergo valence isomerization to the oxaazabicyclo[3.1.0]hexenyl anions ( / 2 ) - ( 1 4 ) , forming a new sigma
bond at the price of two rt-electrons. Theory of valence isomerization of heterotropilidenes (2)e(3)['53 1 6 ] clearly favors the
"pyrrole oxide" anion (13), whose negative charge is not
localized in the three-membered ring and which also forms
the highly stable 1-azaallyl anion system[221.This situation
is confirmed by analysis of the molecular orbitals of the reactant ( 1 1 ) and the products (12)-(14)[221and by calculating
the energy profile of the valence isomerizations. Reaction
simulation leads to the curve shown in Figure 2. Accordingly,
valence isomerization of (11) to (13) not only requires a
lower activation energy than valence isomerization of ( I I )
to (12) or (14), but the anion (13) also has a lower energy
than theanions (1 I ) , (IZ), and ( 1 4 ) ; i.e. kinetic and thermodynamic arguments favor formation of (13).
Reaction course
cesse~[~'!The intramolecular nature of the rearrangements
( I 9) + (18) and ( I 3) ( 1 7 ) and the modest dependence
of the cycloreversion (16)- (19) upon pH and substituent
effects likewise support this
Oxazines (lo), R 2 = H , devoid of substituents in position
4 furnish unstable aldimino ketones (1 9) by proton-catalyzed
ring cleavage of the intermediate pyrrole oxides ( 1 5 ) . Dimerization and dehydration leads to azamerocyanines ( 2 1 )
(R' = CbH5: h,,,=456 nm; log&= 3.82)""l.
4H-3,l-Benzoxazines (22) are transformed into 3H-indole
derivatives (23) on base treatmentL3']; a common feature
of this reaction and the rearrangement (13) + (19) is the
rupture of the C-0 bond. Intramolecular rearrangement
of the R 2 group does not occur, owing to the energetics
of benzoannelation.
Attempts to trap the oxazinyl anion ( 1 1 ) or the valence
isomers (12)-( 14) by anionic polar cy~loaddition['~.
3 1 1 with
electron deficient olefins lead to interesting reactions. Reaction
of (10) or (16) with fumaronitrile in the presence of butyllithium,THF affords compounds whose spectroscopic data indicate the tricyclic structure (24)[281.Both ( I I ) and ( 1 4 ) represent potential starting compounds for this anionic cycloaddition.
Under the same conditions, reaction with tetracyanoethylene gives good yields of 2-azabicyclohexenes ( 2 5 ) , which
exist in solvent-dependent equilibrium with 2,3-dihydropyridines (26)[291.This unusual reaction of tetra~yanoethylene[~~]
is possibly preceded by an oxidation to tetracyanoethylene
oxide with the anion (13) acting as oxidizing agent; the pyrrolyl anions react with tetracyanoethylene oxide with formal
loss of mesoxalonitrile to form the compounds (25) and/or
(26) which eliminate hydrogen cyanide and quantitatively
give 3-pyridinecarbonitrile (27)[291.
Fig. 2. Electrocyclic ring contraction of the I.3-oxazmyl anion ( 1 1 ) . Energy
profile calculation by reaction simulation.
Base treatment of (10) affords weakly yellow compounds
that are labile in protic media; spectroscopic findings and
the molecular orbital calculations mentioned above d o indicate
the pyrrole oxide structure ( 1 6 ) . Moreover, this structure
also derives support from the chemical reactions shown in
Scheme 1[221. The action of triethyl phosphite and triphenylphosphane converts (16) into the pyrrole 1/51, In a protic
medium, rapid cycloreversion of ( 1 6 ) to the imino ketone
( 1 9 ) is observed. The latter compound is transformed into
2-pyrrolin-5-one (18) on heating["]'; (18) can be obtained
directly from (16) in a thermal reaction, the UV spectrum
indicating intermediacy of the imino ketone (19).
Anion (13) rearranges to anion (1 7) above O"C~'21;delocalization of the negative charge over five centers to form a
resonance system having terminal sites of high electronegativity probably favors this reaction course. Protonation furnishes
the less well known 2-pyrrolin-4-ones (20)[261.
The low activation energy of the above thermal reactions
suggests that they are symmetry-allowed pericyclic pro-
1% C N
These reactions convey an idea of the high energy content
of the oxazinyl anion ( 1 1 ) which on protonation undergoes
stepwise transformation into the four isomers of greater thermodynamic stability ( 1 6 ) , (18), ( 1 9 ) , and (20).
The pronounced nucleophilic character of the Rrt-system
( I / 1 is also suspended by a two-electron transfer. Such electron
transfer was observed during the action of ( 1 1 ) on benzaldehyde. Apart from the products of the base-catalyzed Canizzaro
reaction, an excess of benzyl alcohol and. after aqueous work-
up, the hydrolysis product of 1.3-oxazinium salt[2d.2 8 1 are
H R2
2.1.2. t,3,5-Oxadiazinyl Anions
Basically comparable reactions are observed on anion formation from the 4H-1,3,5-oxadiazines ( 2 8 ) , readily obtained
by polar c y ~ l o a d d i t i o n (Scheme
Reaction with nbutyllithium in T H F at -80°C proceeds via the 1,3,5-oxadiazinyl anion ( 2 9 ) and the anion ( 3 2 ) , formed especially rapidly
owing to its 1,3-diazaallyl anion structure, to give the rearranged imidazolinones ( 3 3 ) or the 4H-imidazole ( 3 0 ) arising
therefrom by action of excess n-butyllithium; on reaction of
(28) with Na/K alloy, ( 3 2 ) is reduced to the 1H-imidazole
( 3 1 ) [ 2 8 JThus
the additional nitrogen atom favors ring contraction of ( 2 9 ) to ( 3 2 ) and subsequent reactions, although
the charge density at C2 and C 6 does not differ in anion
Scheme 3
Thus it becomes obvious that these oxepin-analogous
anionic systems have only a slight formation tendency and
a high reactivity, provided they do not possess any special
and hence energetic, features. Valence isomerizations affording systems analogous to benzene oxides are directed by electronegative ring members of appropriate ligands.
2.2. Azepine-Analogous Systems
2.2. I . 1,4-Dihydropyrazines and Dihydropyrazinyl Anions
2.1.3. Pyranyl Anions
How effectively the bicyclic compounds with 1-azaallyl anion or 1.3-diazaallyl anion systems stabilize the negative charge
(see Schemes 1 and 2) is underlined by the behavior of 4Hpyrans ( 3 4 ) towards strong bases[331(Scheme 3). Action of
butyllithiumflHF on ( 3 4 a ) at -80 to -120°C produces
only slight amounts (less than 3 % ) of the pyranyl anion
( 3 5 a ) as a stable blue-violet solution. A low yield of the
cyclopentadiene derivative ( 3 7 a ) is formed, presumably via
the anion ( 3 6 a ) , with a large excess of butyllithium. Only
on use of lithium diisopropylamide as base is an equilibrium
concentration of anion (35 a ) formed (detectable by deuteration). Thence a pK, value of 37+2 can be deduced for the
triphenylated pyran ( 3 4 ~ ) 73].-The
[ ~ ~ . 2,6-diphenylated 4Hpyran ( 3 4 b ) still affords the blue anion ( 3 5 b ) with lithium
diisopropylamide; it could be detected by deuteration (35 %). Anion formation from unsubstituted 4H-pyran ( 3 4 c )
could not be detected even by UV spectroscopy.
This result clearly illustrates the low tendency of 4H-pyrans
( 3 4 ) to transform into systems formally containing eight nelectrons. This phenomenon is so striking because ring strain
and formation of an ally1 anion system[35]rule out valence
isomerization of ( 3 5 ) to ( 3 6 ) as an energetic alternative.
Only when reaction is carried out at -30°C and above does
the activation energy suffice for irreversible subsequent reactions starting from ( 3 5 a ) and (35 b ) ; the resulting cyclopentadiene dimers ( 3 9 a ) and ( 3 9 b ) , respectively, are formed via
1.4-Dihydropyrazine is isoelectronic with cyclooctatetraene
and 1H-azepine. As long ago as 1893, Mason and Winder[37J
thought they had synthesized the N,N'-dibenzylated l.4-dihydropyrazines ( 4 0 ) and (42) (Scheme 4). Chen and Fowler[381
were able to show, however, that 1,2-dihydropyrazines ( 4 1 )
and ( 4 3 ) must have been formed. The electronic destabilization of 1,4-dihydropyrazines is clearly removed by a 1,3-rearrangement[39].This process is probably facilitated by the high
migratory aptitude of the benzyl group.
The rearranged compounds (41) and (43) should be convertible into anionic 8x-systems by the action of bases, leading
I' 4 4 )
it = A r y l
Scheme 4
Angrw. Chem. intrrnar. Edit.
1 Vol. 14 ( I Y 7 5 ) f No. 9
to loss of the proton attached to the quaternary ring C atom.
In fact, treatment of, e. g. ( 4 3 ) , with butyllithium initially
produces a dark red solution from which a yellow compound
isomeric with the starting compound is obtained ; however,
this product has the diazabicycloheptene structure ( 4 6 ) [ 4 0 !
The color of the reaction solution can be taken as indicating
generation of a small amount of the expected dihydropyrazinyl
anion ( 4 4 ) . However, since the negativecharge is not favorably
delocalized in a possible subsequent product, no further regrouping occurs. Instead. a benzyl anion system ( 4 5 ) is produced in an equilibrium mixture ;after intramolecular nucleophilic
addition giving ( 4 6 ) the negative charge is stabilized in a
1-azaallyl anion.
In order to suppress formation of the benzyl anions ( 4 5 ) ,
an attempt was made to produce the 1,2-dihydropyrazines
( 4 9 ) similarly by dimerizing condensation of arylaminoketones ( 4 7 ) via the 1,4-dihydropyrazines ( 4 8 ) (Scheme 5). However, depending upon the aryl substituent, one surprisingly
obtains 1,4-dihydropyrazines (50) or the 1,4-dihydropyrazines
( 5 4 ) by double substituent shift with ( 5 1 ) as likely intermediate[40-421
Formation of ( 5 0 ) is due to production of diphenacylaniline
from ( 4 7 ) . The reason underlying the double rearrangement
( 5 0 ) + ( 5 4 ) has not yet been established. Steric constraints
probably play a crucial role. Regeneration of the 1,Cdihydropyrazine system ( 5 4 ) from (51) show the formation tendency
and thermal stability of the resulting 1,4-dihydropyrazines
(50) and ( 5 4 ) to be fairly high, and synthesis of further
1,4-dihydropyrazines substantiates this conclusion. Thus derivatives of 1,4-dihydropyrazine have been prepared by Chen
and Fowler[431using electron-withdrawing substituents, by
Sdzbach and Iqba/[441employing trimethylsilyl substituents.
and by L o w and A k h t ~ rmainly
[ ~ ~ ~by use of relatively immobile alkyl groups on the two nitrogen atoms. The last-mentioned research group has recently also shown that the 1,3-rearrangement is to be classed as an antara-suprafacial [1,3]sigmatropic shift[4",471.
The reason for this unexpected stability can only lie in
a special conformation opposing cyclic delocalization of the
eight electrons. This was confirmed by X-ray structural analysis
of a compound of structure (50)[481(see Figure 3).
Fig.3. X-ray data of 1,4-bis(4-chlorophenyI)-2,6-diphenyl1.4-dihydropyrazine
(50). R ' =4-chlorophenyl, R2=phenyl [48].
According to Figure 3, the four C atoms of the 1,4-dihydropyrazine skeleton form a plane while the two nitrogen atoms
(N', N4) are arranged at different distances above this plane;
the overall skeleton consequently has a quasi-boat shape.
Nevertheless, deviations from planarity are not so pronounced
as to largely preclude n- and n-electron d e l o c a l i z a t i ~ n [ ~ ~ J .
The position of the aryl ligand on N ' leads, however, to
a separation of the electronic system into a delocalized, possibly homoaromatic system of six n-electrons (C', C3, N4, C5.
C") and an almost orthogonal lone pair on N'. This structural
finding gives grounds for suspecting that six-membered, formally antiaromatic ring systems can counteract electronic
destabilization by ligand conformations which substantially
reduce or eliminate delocalization of the eight 7r-electrons.
Thus a state is approached such as is attainable only by
skeletal bending in the case of eight-membered rings. This
ligand-control of stability of I .4-dihydropyrazines[', 421 should
play a greater role than the deviations of the cyclic skeleton
from planarity["', '"1. Confirmation of this result is provided
by investigations of conformation and nitrogen inversion
in 1,5-dihydroisoalloxazines (56)-models
for dihydroflavin-and is not a consequence of bulky ligands attached
to the pyrazine
(see also Section 4).
-- A r y l ;
R3 = Alkyl, A c e t y l
Scheme 5
Anyen.. Chern. ;trrerttur. Edir. // Kd. 14 f 1 9 7 5 ) I. No. 9
The doubly rearranged N-aryl-l,4-dihydropyridines( 5 4 )
(see Scheme 5 ) are suitable for anion formation. The anions
obtained by treatment with strong bases at low temperature
are dark red. However, they do not display rearrangement
or valence isomerization to form ( 5 2 ) . Formation of a 2-azaal-
lyl anion system and the fact that the new cr-bond-as in
the case of azepine[15~'h.521-'
IS unstable give reason for
expecting this finding. The dihydropyrazinyl anions ( 5 3 )
undergo N-alkylation and N-acylation at low temperature;
the reaction products are 1,4-dihydropyrazines ( 5 5 ) .
nucleophilic acylation has nevertheless been observed. In this
way the quinolylmethanols (65 h) have been obtained from
(62 b)159'.
2.2.2. Dihydropyridyl and Dihydroquinolyl Anions
The results obtained for the pyrans (see Section 2.1.3) suggest
that dihydr~pyridined'~',havingno ligands capable of stabilizing negative charges, will not display any pronounced tendency
to form anions. This was also observed (Scheme 6). The triphenylated dihydropyridine ( 5 7 a ) could not be demonstrably
converted into the anion
by lithium diisopropylamide
at low temperature; i.e. the pK, value of ( 5 7 a ) is greater
than 40. A comparably low acidity is found for the N-dimethylamino-compound (57b) ; above -20°C. however, it decomposes irreversibly zia the anion (586) into lithium dimethylamide and the pyridine derivative (59 h).
Under drastic reaction conditions the C-unsubstituted
dihydropyridines ( 5 7 c ) , (57d), (61 c), and ( 6 1 d ) are transformed into the equilibrium mixture by potassium tert-butoxide in DMSO at elevated temperature[54.551. However, this
reaction might proceed with participation of DMSO anion
in a multicenter process[5h! Surprisingly N-phenyl-I ,2-dihydropyridine (57d) can also be deprotonated at the methylene
group to a slight extent by lithium diisopropylamide in T H F
at low temperature. The phenyl ligand may play an important
part in the reaction.
Annelation of a benzene ring significantly raises the acidity
This acidification should
of the dihydropyridine
be especially pronounced in the Reissert compounds ( 6 2 a )
when induced by the N-acyl and 2-cyano group (Scheme
7). The tendency to regenerate the quinoline system ( 6 4 )
[seealso thecleavageof ( 5 7 b ) l makes the anions ( 6 3 ) suitable
for use as reagents for nucleophilic acylation. The simplest
case would be synthesis of aldehydes with protons. Although
aldehydes or their derivatives have not yet been detected
during anion formation in protic media[581,an intramolecular
(62) R2-k=0
( a ) , R' = CN, R2 = Ar;
( b ) , R'
R2=A r
Scheme 7
Apart from acidification by benzoannelation and by electron-withdrawing ligands at the centers 2,4, and 6 cumulating
negative charge in the anion, results gathered for the 1,3-oxazines and 1,3,5-oxadiazines (Sections 2.1.1 and 2.1.2) have
shown that anion formation will be promoted by electron-withdrawing ligands in positions 3 and 5 above all when valence
isomerization to a bicyclo[3.1.0]hexeny1 anion ensues. Since
Nature employs such a system for hydrogen transfer in NADH
it seemed logical to examine whether deprotonation and electron transfer should be considered as a valid alternative to
the generally accepted hydride transfer mechanism1h0!
For this purpose the dihydropyridines (57e), (60e), (60f),
(61 e), and (61f) were treated with lithium diisopropylamide
(Scheme 6) and lithium salt formation detected by deuteration
and alkylati~n['~!It could be unequivocally shown that these
lithium saltsare not formed by deprotonation at the methylene
group and prototropism; instead direct exchange of H2occurs
with (60e), (60f), (61 e ) , and (61f), and direct exchange
of H4 in the case of (57e). The adjacent location of the
nitrile or carboxamide group assists this process by complex
formation-a phenomenon that has also been observed in
Hence a further argument is obtained for
the hydride transfer
The very modest tendency
to undergo valence isomerization to give a bicyclic system,
which is even more pronounced for the dihydropyridyl anions
(58), owing to the negative charge and the greater ring strain,
than for the azepines should be the principle cause for the
very slight inclination to form (58).
23. Systems Analogous to Thiepin
2.3.1. 1,3-Thiazinyl Anions
Thiepin-like six-membered 8x-systems warrant particular
attention since they should provide further information about
the stability and possible synthesis of the difficultly accessible
thiepinsr6*]. Systems isoelectronic with the thiepins can be
obtained in the form of 1,3-thiazinyl anions ( 6 9 ) as highly
unstable dark violet solutions by the action of strong bases
on the 1,3-thiazines (66)-(68) ;however, their reaction products are not the anion (70) but the pyrrole ( 7 I ) (Scheme
8)[409 631. Indoles are formed in like manner from 4H-3,l-benzothiazines by action of a
This result accords with, expectations. On going from the
1,3-oxazinyl (see Section 2.1.1) to the 1,3-thiazinyl anion, electronic destabilization should increase owing to the lower electronegativity of the sulfur provided the sulfur makes no particular contribution to stabilization of the negative charge[h51.
The high associated energy content of ( 6 9 ) and the modest
Angew. Chem. inrernar. Edit.
1 Vol. 14 ( 1 9 7 5 ) 1 No. 9
stability of the episulfide bond in the anion ( 7 0 ) lead even
at very low temperature to a fast irreversible elimination
of sulfur. Apparently the thiazinyl anions ( 6 9 ) behave like
the thiepins, whose synthesis is so difficult precisely because
of this rapid desulfuration.
(Scheme 10)‘h91.The high-energy 4H-1,3,4-thiadiazines (73)
occur as intermediates[”’’.
An analogous result can be accomplished by formation
of theanion ( 7 6 ) at considerably lower temperature^[^"'. Temperature variations indicate that the 1,3-thiazinyl anions ( 6 9 )
are not stabilized to the Sx-anion ( 7 6 ) by introduction of
the additional nitrogen atom in position 4 although MO
calculations on ( 6 9 ) (see Fig. 4) attribute a large partial negative charge to this center. Anion formation is rate determining;
valence isomerization to ( 7 7 ) and elimination of sulfur or
episulfide ring opening to give ( 7 4 ) or ( 7 5 ) follow rapidly.
The various conditions of pyrazole formation on action of
acids and bases show the 1,3,4-thiadiazinyl anions ( 7 6 ) to
have a very high energy content.
Scheme 8
The charge density distribution (see Figure 4) partly explains
the facile intramolecular linkage of a new CC bond. However,
consideration of the formally close resemblance of this reaction
to the important method of CC bond formation developed
by Eschenmosrr[661(Scheme 9), which requires a phosphane
and generally higher temperature, clearly reveals the high
energy content of ( 6 9 ) promoting the reaction.
Scheme 10
Synthesis of imidazoles from 4H- 1,3,5-thiadiazines cia the
corresponding anions proceeds with comparable ease1711.
Scheme 9
2.3.3. Thiopyranyl Anions (“Thiabenzene Anions”)
The thiazinyl anions ( 6 9 ) can be obtained as essentially
stable solutions below - 100°C. They can be quantitatively
deuterated, alkylated, and acylated at - 100”C[28.41* 6 3 ] . Their
stability and their ambivalent character depend not only on
the base
6 3 . 6 7 1 but also on salt additives and above
all on added complexing agents for the cations. The reason
lies in the presence of more or less intimate ion pairs or
free ions. In accord with the charge density distribution (Fig.
4), however, the 6-substituted 6H-thiazine ( 6 8 ) is the major
product. O n addition of crown ethers for cation complexation,
the free anions are generally transformed quantitatively into
the 6-substituted 6H-thiazines (68). This is particularly significant for the utilization of ( 6 9 ) in synthetic methods[’].
7 -028
+ 0.16
Fig. 4. Charge density calculations for the 1,3-thiazinyl anion (69) and
the thiopyranyl anion (“thiabenzene anion”) ( 8 0 ) [68].
2.3.2. Thiadiazinyl Anions
Acid-catalyzed ring contraction of 6H-1,3,4-thiadiazines
(72) generally requires elevated reaction temperatures; sulfurfree pyrazoles ( 7 4 ) and 4-pyrazolethiols ( 7 5 ) are obtained
Angrn. Chem. intemat. Edit. J Vol. 1 4 1 1 9 7 5 ) J N o . 9
In contrast to the thiazinyl and thiadiazinyl anions, the
thiopyranyl anions ( 8 0 ) do not possess an electronegative
from the sulfur atom-for acceptance and
stabilization of negative charge. Moreover, there is no charge
density difference (see Fig. 4) at C 2 and C h which would
promote formation of a new CC bond to give the anion
(82). Irreversible sulfur elimination from (81) to yield the
low-energy cyclopentadiene (82) should nevertheless favor
this reaction course.
The thiopyranyl anion ( 8 0 ) displays an entirely new behavior on reaction (Scheme 1 1 ) ~ 7 2 . 7 3 !Starting, e.g. from the
triphenyl substituted thiopyran ( 7 8 ) or ( 7 9 ) , R = C6H 5 , even
moderately strong bases lead to a solution of the ambivalent
anion (80) which is stable in an inert atmosphere and is
dark red at room temperature.
Hence a pK, value of 19Sk 1 is derived (see Table 1)[731.
Only on action of triphenylphosphane at room temperature
can the sulfur-free cyclopentadiene (82) be produced. Deuteration to give 2-deuteriothiopyran ( 8 3 ) , R’=D, and likewise
the alkylation and acylation proceed smoothly, generally
affording 4-substituted thiopyrans (85)[721.Reaction with
“hard” alkylating reagents particularly at low temperatures
(diphenyliodonium salts, methyl fluorosulfate) furnishes a
stable red solution which according to UV measurements
contains a high proportion of Ih4-thiabenzene ( 8 4 ) [ 2 87 .3 1 .
Thiabenzenes were produced by Price et
and Mislmv et a / . [ 7 6 by
1 another route. Possibly,
reaction of ( 8 0 ) with electrophiles leads to transient formation
of the easily rearrangeable thiabenzenes (84) in other cases
too. Calculations of charge distribution (see Fig. 4) and investi587
gations on the phosphabenzene
support for a reaction course of this kind.
could provide
up the excess electron pair. Since the oxygen and nitrogen
atoms do not possess such orbitals the anionic cyclic 8n-system
will have a higher energy content in this case.
However, a difference of ca. 17 pK, units between the anal~.~~]
ogous oxygen and sulfur system is so e x ~ e p t i o n a l ~that
different electronic configurations must be assigned-as sugI
Fig. 5. Model for electronic configuration of thiabenzene according to Denar
Scheme I I
The unexpectedly high acidity of thiopyran, which is also
observed for 2H-thiochromene and for phosphacyclohexadiene[77- 791 and the non-occurrence of spontaneous ring contraction to give cyclopentadiene probably have the following
explanation: thiopyranyl anions (80) are not cyclic 8n- but
cyclic 6n-systems, as shown by the resonance structure (806)
having an electron decet and negative charge at the sulfur,
i . r . (80) is better described as a thiabenzene anion[721.
According to D e ~ a r ~the
~ ~thiabenzene
system is non-aromatic;
its energy lies between those of the aromatic 6n and antiaromatic 8n-systems. In this model (see Fig. 5) two orthogonal
d-orbitals of the sulfur are delocalized into the n-system, affording a cyanine anion system whose termini lie in the sulfur
atom. Other models agree less well with the observations
mentioned[74*751.Formation of thiabenzenes ( 8 4 ) from the
thiabenzene anions (80) is not entirely compatible with the
ylide structure derived for thiabenzenes by Hortmann et a/.[7s1
and Mislow et a/.[761.
The pK, values and the half-wave potentials in Table 1
clearly demonstrate the anion-stabilizingeffect of sulfur atoms,
which has been interpreted in various ways. The low-lying
d-orbitals[81]or antibonding o-orbitals[821might possibly take
gested-to the two systems. In this context, all available evidence indicates the concept of more or less pronounced cyclic
delocalization of eight n-electrons in systems with first-row
ring members to be the principal factor. Contrary to expectation, however, the thiazine system is less acidic and the second
half-wave potential is more negative than in the corresponding
thiopyran system although the more electronegative nitrogen
is present as ring member.
3. Seven-Membered Anionic Systems Having Eight
A considerably lower electronic destabilization is expected
for seven-membered 8n-systems than for six-membered 8n-systems (see Section 1.1). The cycloheptatrienyl anion[851and
its heptaphenyl derivativeIa6]were generated a long time ago;
they proved to be thermally unstable1'*! Furthermore, unsubstituted cycloheptatriene (having a pK, value of +36) is far
less acidic than cyclopentadiene (pK,= 1 8)Ia59871.
In the case of the 4H-1,2-diazepines (86), which do not
undergo valence isomerization[881,transformation into 1,2-diThus
azepinyl anions (87) is again seen to be
on treatment with n-butyllithium and tert-butyllithium at low
temperature, (86) does not yield the expected anions (87)
but products of addition to the C3N2 double bond. This
is a clear indication of the low acidity of the 4H-1.2-diazepines
(86). Partial anion formation only becomes possible with
lithium diisopropylamide, a compound exhibiting pronounced
Table I. pK, values (in T H F ) [73] and polarographic half-wave potentials (reference electrode, calomel electrode
ISII u r i i k d ) : solvent, acetonitrile: supporting electrolyte, tetramethylammonium tetrafluoroborate) [28].
Type ( 1 1 )
Type ( 8 0 0 )
Type 169)
Type ( 8 0 ~ )
>40 [a]
37 5 2 [dl
19.5 f 1 [a, b]
22.5+ I [b]
3 2 F 1 [b]
- 1.51
- 1.31
- [CI
- 1.37
[a] Thermodynamic acidity
[b] Kinetic acidity
[c] Cyclic voltammetry also field to give a reversible redox potential 1841.
Angen. Chem. inremar. Edit. / Vol. 1 4 ( 1 9 7 5 )
1 No. 9
steric hindrance; hence it can be deduced that the pK, value
of compounds (86) is greater than +30.
In accord with the theory of Hoffmann["' and Giinther["]
no valence isomerization could be observed on anion formation. Only on coupling with pyridine formation to give ( 8 9 ) ,
i. e. by reaction with Na/K alloy, can intermediate valence
isomerization be forced to occur. Thus the 1,2-diazepine anions
(87) behave similarly to C-unsubstituted lH-1,2-diazepines,
which suffer comparable irreversible changes on heating[8y$I'.
Consequently the effect of electronic destabilization on the
anions (87) cannot be neglected.
R = Aryl
Apart from the above reactions, seven-membered heterocycles and particularly the intensively studied benzodiazepines
exhibit numerous interesting valence isomerizations and rearrangements["] to which the cyclic delocalization of eight nelectrons must make a significant contribution.
4. Biological Systems
The question of the stability of six-membered heterocycles
containing eight delocalizable n-electrons not only possesses
purely chemical interest but is also of considerable significance
for the transfer of a formal hydride equivalent from the CH
substrate onto heteroaromatic coenzymes such as flavin ( 9 0 )
and nicotinamide adenine dinucleotide (NADH)and its resolution into one-electron equivalents must necessarily involve
a formal 8n intermediateL4*-y21.
Flavin coenzyme catalyzed hydrogen transfer from substrates of CH active hydroxy and amino compounds leads
to productsofaddition to the 1,4-diazadiene system of oxidized
flavin ( 9 0 ) . In this reaction a 1,4-dihydropyrazine system
is generated transiently in the dihydroflavin (91), which is
transformed into oxidized flavin and a carbonyl compound
(901 O
by dehydrogenation["! As in the 1,4-dihydropyrazines (Section 2.2.1). the stability of ( 9 1 ) is largely dependent on the
planarity and especially on the position^[^'^ y31 of the N- and
N'-ligands. In this way the wide range of potentials open
to the flavoproteins is subject to control-which is of particular
Anyrw. Chem. i n f e m a f .Edit.
1 Vol. 14 ( 1 9 7 5 ) 1 N o .
biological significancec5'.'*I. In addition, a possible explanation of the surprisingly high O2 affinity of such potentially
antiaromatic systems is suggested : reaction of organic singlet
compounds with triplet oxygen is known to be spin-forbidden
and is therefore slow provided it does not proceed via radicals.
However, radicals have never been observed in biological
flavin-dependent O 2 activationCy2.
Some bioluminescing organisms contain luciferins which
formally display cyclic 8 n - ~ y s t e r n s [ ~As
~ ]an
. example we can
consider the luciferin ( 9 2 ) from Renilla renformis. It has
not yet been established, however, whether the dihydropyrazine system possesses specific biological significance for the
luminescence property beyond its enhanced electron donor
In dihydronicotinamide, NADH possesses a system which
could transform into a cyclic 8n-system via deprotonation.
Studies performed on model compounds (see Section 2.2.2)
nevertheless suggest that such a reaction fails to occur, owing
to the high energy of the dihydropyridyl anion, and direct
hydride transfer to the substrate with formation of NAD+
is unequivocally favored, i. e. the carboxamide group in position 3 stabilizes the labile dihydropyridine.
Studies on the benzene oxide-oxepin problem acquired a
new dimension when it was discovered that the oxidative
metabolism of arenes proceeds via benzene oxide-oxepin intermediates (see Scheme 12)[96.971. Recently, Frjdrnann et
ul.ry8* found that the enzymatic oxidation of porphobi-
- Ra
R Q + R e o
Scheme I2
linogen ( 9 3 ) , the key intermediate in porphyrin and corrin
syntheses, leads to the tautomeric pyrrolinones ( 9 5 u ) and/or
(95 b ) . Comparison of this reaction with the enzymatic oxidation of arenes reveals a close structural analogy. It seems
obvious to conclude that the pyrrole oxide ( 9 4 ) is the reaction
intermediate[1001.Supporting evidence comes from the rearrangements observed with the 1,3-oxazinyl anion ( 1 1 ). Facile
rearrangement of the pyrrole oxides ( I 6) to the pyrrolinone
(18) related to ( 9 5 ) and the possible reduction of ( 1 6 ) to
the pyrroles ( 1 5 ) follow parallel courses (Section 2.1.1). The
marked hydrolytic lability of the pyrrole oxides (16) and
( 9 4 ) in comparison with the benzene oxides will disfavor
direct detection of ( 9 4 ) as an intermediate of porphobilinogen
5. Summary and Outlook
Available factual material shows: negatively charged sixmembered and presumably also seven-membered cyclic 8x-systems are destabilized by resonance if the ring is composed
of first row atoms. Destabilization is manifested in reduced
acidity of the starting materials and enhanced reactivity of
the anions. The thiopyranyl and phosphabenzene anion show
that ring members from the second row can, at least partly,
accommodate the excess electron pair in a low-lying orbital.
The overall system thus experiences considerable stabilization.
A significant role in determining the observed reactions is
played by electron-withdrawing sites in or attached to the
ring. In the specific case of uncharged six-membered cyclic
8x-systems, of which only 1,4-dihydropyrazine has been considered in this article, electronic destabilization is probably
reduced by ring deformations and particular ligand conformations.
The more or less enhanced energy content of these systems
permits surprising valence isomerizations, rearrangements,
fragmentations, and reactions with electrophiles at very low
temperatures. Only few of the resulting preparative pathways
have so far been implemented. Furthermore, anion formation
and the reactivity of the resulting anions have not yet been
examined in many cases. Nor has any work been done on
the possible stabilizdtion of these systems by transition metals.
The occurrence of special ring inversion barriers could be
important in the future investigation of spectroscopic properties[51, 1011
Some of these systems are excellent models for biologically
relevant systems. Further model studies should help us to
answer questions of electron-transfer properties and proclivity
to radical formation, as well as those concerning the influence
of ligands and conformations on redox properties, to mention
just a few.
I am particularly indebted to my co-workers mentioned in
the hibliographji ,fbr their assistance in the inwstigations described, to Prof:R. Gleitrr and Prof: P. Hemmerich ,for stinidatiny
discussions, and the Ge.~ellscha~
Deutscher Chemiker for their
recognition of these studies. Thanks are also due to the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie for financial support.
Received: December 30, 1974 [A 69 IE]
German version: Angew. Chem. 87. 603 (1975)
Based on a lecture delivered at the Chemiedozententagung. Stuttgart.
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ca. 0.58 [22].
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43, 359 (1973).
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and M. Dimmler, to be published.
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The Pyruvate Dehydrogenase Multienzyme Complex
By Ferdinand Hucho[*l
The three enzymes pyruvate dehydrogenase, dihydrolipoamide transacetylase, and dihydrolipoamide dehydrogenase constitute the pyruvate dehydrogenase multienzyme complex of E .
coli; in mammals the complex also contains a kinase and a phosphatase. Multienzyme complexes
are structural, functional, and regulatory units enabling the organism to operate more economically than with single enzymes. The pyruvate dehydrogenase multienzyme complex may stand
at the switch-point between energy metabolism and gluconeogenesis.
1. Introduction
Multienzyme complexes are proteins in which several noncovalently bonded enzymes in constant relative amounts form
a stable and highly ordered association. The enzyme constituents of the complex often catalyze successive steps in a
metabolic sequence. MultienzYme complexes OCCUPY
an intermediate position between cooperating but structurally inde[*] Univ.-Doz. Dr. F. Hucho
Fachbereich Biologie der Universitat
D-2775 Konstanz. Postfach 733 (Germany)
Angew. Chrm. inrcruat. Edit. / Vol. 14 (1975)
/ No. 9
pendent “soluble” enzymes on the one hand and membranebound insoluble enzyme systems on the other, and can thus
serve as models for both groups. Typical examples from the
group of structurally independent soluble enzyme systems
are the enzymes of glycolysis or of the tricarboxylic acid
cycle, while the insoluble enzymes include the respiratory
chain proteins of the mitochondria1 membrane or the photosynthesis proteins of the chloroplast membrane. Examples
of multienzyme complexes are the cc-keto acid dehydrogenases,
fatty acid synthetase, and the enzyme complexes that take
part in the synthesis of aromatic amino acids.
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